Understanding the diversity of membrane lipid composition

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  • 1 Department of Biochemistry and National Centre for Competence in Research in Chemical Biology, Sciences II, University of Geneva, Geneva, Switzerland.
  • PMID: 29410529
  • DOI: 10.1038/nrm.2017.138

Cellular membranes are formed from a chemically diverse set of lipids present in various amounts and proportions. A high lipid diversity is universal in eukaryotes and is seen from the scale of a membrane leaflet to that of a whole organism, highlighting its importance and suggesting that membrane lipids fulfil many functions. Indeed, alterations of membrane lipid homeostasis are linked to various diseases. While many of their functions remain unknown, interdisciplinary approaches have begun to reveal novel functions of lipids and their interactions. We are beginning to understand why even small changes in lipid structures and in composition can have profound effects on crucial biological functions.

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  • Research Support, Non-U.S. Gov't
  • Cell Membrane / metabolism*
  • Eukaryota / metabolism
  • Homeostasis / physiology
  • Membrane Lipids / metabolism*
  • Membrane Lipids

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7.3: Lipids

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Learning Objectives

  • Describe the chemical composition of lipids
  • Describe the unique characteristics and diverse structures of lipids
  • Compare and contrast triacylglycerides (triglycerides) and phospholipids
  • Describe how phospholipids are used to construct biological membranes

Although they are composed primarily of carbon and hydrogen, lipid molecules may also contain oxygen, nitrogen, sulfur, and phosphorous. Lipids serve numerous and diverse purposes in the structure and functions of organisms. They can be a source of nutrients, a storage form for carbon, energy-storage molecules, or structural components of membranes and hormones. Lipids comprise a broad class of many chemically distinct compounds, the most common of which are discussed in this section.

Fatty Acids and Triacylglycerides

The fatty acids are lipids that contain long-chain hydrocarbons terminated with a carboxylic acid functional group. Because of the long hydrocarbon chain, fatty acids are hydrophobic (“water fearing”) or nonpolar. Fatty acids with hydrocarbon chains that contain only single bonds are called saturated fatty acids because they have the greatest number of hydrogen atoms possible and are, therefore, “saturated” with hydrogen. Fatty acids with hydrocarbon chains containing at least one double bond are called unsaturated fatty acids because they have fewer hydrogen atoms. Saturated fatty acids have a straight, flexible carbon backbone, whereas unsaturated fatty acids have “kinks” in their carbon skeleton because each double bond causes a rigid bend of the carbon skeleton. These differences in saturated versus unsaturated fatty acid structure result in different properties for the corresponding lipids in which the fatty acids are incorporated. For example, lipids containing saturated fatty acids are solids at room temperature, whereas lipids containing unsaturated fatty acids are liquids.

A triacylglycerol, or triglyceride, is formed when three fatty acids are chemically linked to a glycerol molecule (Figure \(\PageIndex{1}\)). Triglycerides are the primary components of adipose tissue (body fat), and are major constituents of sebum (skin oils). They play an important metabolic role, serving as efficient energy-storage molecules that can provide more than double the caloric content of both carbohydrates and proteins.

A diagram showing a triglyceride is made of a glycerol and three fatty acids. Glycerol is a 3 carbon chain with an OH on each carbon. The H on each OH is highlighted. Fatty acids are long carbon chains with a C that has an OH and a double bonded O at the end. The OH of this C is highlighted. Three fatty acids are shown. Each fatty acid binds to one of the O’s from the OH groups on each Carbon on glycerol. The result is a triglyceride (or neutral fat) and 3 water molecules.

Exercise \(\PageIndex{1}\)

Explain why fatty acids with hydrocarbon chains that contain only single bonds are called saturated fatty acids.

Phospholipids and Biological Membranes

Triglycerides are classified as simple lipids because they are formed from just two types of compounds: glycerol and fatty acids. In contrast, complex lipids contain at least one additional component, for example, a phosphate group (phospholipids) or a carbohydrate moiety (glycolipids). Figure \(\PageIndex{2}\) depicts a typical phospholipid composed of two fatty acids linked to glycerol (a diglyceride). The two fatty acid carbon chains may be both saturated, both unsaturated, or one of each. Instead of another fatty acid molecule (as for triglycerides), the third binding position on the glycerol molecule is occupied by a modified phosphate group.

A drawing of a phospholipid as a large circle with 2 rectangles projecting from the bottom. The circle is labeled hydrophilic head and contains glycerol (which contains 3 carbons). Attached to one of these carbons is a phosphate (which is a phosphorus attached to 4 oxygen atoms). The rectangles at the bottom are both long carbon chains labeled as hydrophobic tails. One of the chains is a straight zig-zag line and is labeled saturated fatty acid. The other has a double bond that creates a bend in the line; this is labeled unsaturated fatty acid.

The molecular structure of lipids results in unique behavior in aqueous environments. Figure \(\PageIndex{1}\) depicts the structure of a triglyceride. Because all three substituents on the glycerol backbone are long hydrocarbon chains, these compounds are nonpolar and not significantly attracted to polar water molecules—they are hydrophobic. Conversely, phospholipids such as the one shown in Figure \(\PageIndex{2}\) have a negatively charged phosphate group. Because the phosphate is charged, it is capable of strong attraction to water molecules and thus is hydrophilic, or “water loving.” The hydrophilic portion of the phospholipid is often referred to as a polar “head,” and the long hydrocarbon chains as nonpolar “tails.” A molecule presenting a hydrophobic portion and a hydrophilic moiety is said to be amphipathic. Notice the “R” designation within the hydrophilic head depicted in Figure \(\PageIndex{2}\), indicating that a polar head group can be more complex than a simple phosphate moiety. Glycolipids are examples in which carbohydrates are bonded to the lipids’ head groups.

The amphipathic nature of phospholipids enables them to form uniquely functional structures in aqueous environments. As mentioned, the polar heads of these molecules are strongly attracted to water molecules, and the nonpolar tails are not. Because of their considerable lengths, these tails are, in fact, strongly attracted to one another. As a result, energetically stable, large-scale assemblies of phospholipid molecules are formed in which the hydrophobic tails congregate within enclosed regions, shielded from contact with water by the polar heads (Figure \(\PageIndex{3}\)). The simplest of these structures are micelles, spherical assemblies containing a hydrophobic interior of phospholipid tails and an outer surface of polar head groups. Larger and more complex structures are created from lipid-bilayer sheets, or unit membranes, which are large, two-dimensional assemblies of phospholipids congregated tail to tail. The cell membranes of nearly all organisms are made from lipid-bilayer sheets, as are the membranes of many intracellular components. These sheets may also form lipid-bilayer spheres that are the structural basis of vesicles and liposomes, subcellular components that play a role in numerous physiological functions.

A lipid bilayer sheet is when there are 2 rows of phospholipids across each other forming a flat surface. The polar heads of all phospholipids are towards the outside of the sheet, and the nonpolar tails are towards the inside. This lipid-bilayer can also form a sphere. The lipid-bilayer forms the surface of the sphere; the  polar heads are on the outside of the sphere and lining the inside space of the sphere. Lipids can also form a single-layer sphere where the outside of the sphere is the polar heads and the nonpolar tails fill the center of the sphere.

Exercise \(\PageIndex{2}\)

How is the amphipathic nature of phospholipids significant?

Isoprenoids and Sterols

The isoprenoids are branched lipids, also referred to as terpenoids, that are formed by chemical modifications of the isoprene molecule (Figure \(\PageIndex{4}\)). These lipids play a wide variety of physiological roles in plants and animals, with many technological uses as pharmaceuticals (capsaicin), pigments (e.g., orange beta carotene, xanthophylls), and fragrances (e.g., menthol, camphor, limonene [lemon fragrance], and pinene [pine fragrance]). Long-chain isoprenoids are also found in hydrophobic oils and waxes. Waxes are typically water resistant and hard at room temperature, but they soften when heated and liquefy if warmed adequately. In humans, the main wax production occurs within the sebaceous glands of hair follicles in the skin, resulting in a secreted material called sebum, which consists mainly of triacylglycerol, wax esters, and the hydrocarbon squalene. There are many bacteria in the microbiota on the skin that feed on these lipids. One of the most prominent bacteria that feed on lipids is Propionibacterium acnes , which uses the skin’s lipids to generate short-chain fatty acids and is involved in the production of acne.

Alpha-pinene is a carbon ring with added carbon projections. Camphor is a carbon ring with added carbon projections and a double bonded oxygen on one carbon. Isoprene is a 4 carbon chain with another carbon attached to carbon 2. Limonene is a carbon ring with a carbon attached to one end and another carbon attached to the other end; this carbon has 2 carbons attached to it. Menthol is a carbon ring with a carbon attached to one end and another carbon attached to the other end; this carbon has 2 carbons attached to it. One more carbon corner has an OH group. Beta-carotene is two carbon rings attached by a long carbon chain.

Another type of lipids are steroids, complex, ringed structures that are found in cell membranes; some function as hormones. The most common types of steroids are sterols, which are steroids containing an OH group. These are mainly hydrophobic molecules, but also have hydrophilic hydroxyl groups. The most common sterol found in animal tissues is cholesterol. Its structure consists of four rings with a double bond in one of the rings, and a hydroxyl group at the sterol-defining position. The function of cholesterol is to strengthen cell membranes in eukaryotes and in bacteria without cell walls, such as Mycoplasma . Prokaryotes generally do not produce cholesterol, although bacteria produce similar compounds called hopanoids, which are also multiringed structures that strengthen bacterial membranes (Figure \(\PageIndex{5}\)). Fungi and some protozoa produce a similar compound called ergosterol, which strengthens the cell membranes of these organisms.

Cholesterol is made of 3 hexagons attached along their edges. The third hexagon has a pentagon attached along an edge. The pentagon has a carbon chain attached to it. Hopene is made of 4 hexagons attached along their edges. The last hexagon has a pentagon. The pentagon has a short carbon chain.

Link to Learning: Liposomes

This video provides additional information about phospholipids and liposomes.

Exercise \(\PageIndex{3}\)

How are isoprenoids used in technology?

Clinical Focus: Part 2

The moisturizing cream prescribed by Penny’s doctor was a topical corticosteroid cream containing hydrocortisone. Hydrocortisone is a synthetic form of cortisol, a corticosteroid hormone produced in the adrenal glands, from cholesterol. When applied directly to the skin, it can reduce inflammation and temporarily relieve minor skin irritations, itching, and rashes by reducing the secretion of histamine, a compound produced by cells of the immune system in response to the presence of pathogens or other foreign substances. Because histamine triggers the body’s inflammatory response, the ability of hydrocortisone to reduce the local production of histamine in the skin effectively suppresses the immune system and helps limit inflammation and accompanying symptoms such as pruritus (itching) and rashes.

Exercise \(\PageIndex{4}\)

Does the corticosteroid cream treat the cause of Penny’s rash, or just the symptoms?

Key Concepts and Summary

  • Lipids are composed mainly of carbon and hydrogen, but they can also contain oxygen, nitrogen, sulfur, and phosphorous. They provide nutrients for organisms, store carbon and energy, play structural roles in membranes, and function as hormones, pharmaceuticals, fragrances, and pigments.
  • Fatty acids are long-chain hydrocarbons with a carboxylic acid functional group. Their relatively long nonpolar hydrocarbon chains make them hydrophobic . Fatty acids with no double bonds are saturated ; those with double bonds are unsaturated .
  • Fatty acids chemically bond to glycerol to form structurally essential lipids such as triglycerides and phospholipids. Triglycerides comprise three fatty acids bonded to glycerol, yielding a hydrophobic molecule. Phospholipids contain both hydrophobic hydrocarbon chains and polar head groups, making them amphipathic and capable of forming uniquely functional large scale structures.
  • Biological membranes are large-scale structures based on phospholipid bilayers that provide hydrophilic exterior and interior surfaces suitable for aqueous environments, separated by an intervening hydrophobic layer. These bilayers are the structural basis for cell membranes in most organisms, as well as subcellular components such as vesicles.
  • Isoprenoids are lipids derived from isoprene molecules that have many physiological roles and a variety of commercial applications.
  • A wax is a long-chain isoprenoid that is typically water resistant; an example of a wax-containing substance is sebum, produced by sebaceous glands in the skin. Steroids are lipids with complex, ringed structures that function as structural components of cell membranes and as hormones. Sterols are a subclass of steroids containing a hydroxyl group at a specific location on one of the molecule’s rings; one example is cholesterol.
  • Bacteria produce hopanoids, structurally similar to cholesterol, to strengthen bacterial membranes. Fungi and protozoa produce a strengthening agent called ergosterol.

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Introduction

Photoreceptors, acknowlegment, cell membrane lipid composition and distribution: implications for cell function and lessons learned from photoreceptors and platelets.

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Kathleen Boesze-Battaglia , Richard J. Schimmel; Cell Membrane Lipid Composition and Distribution: Implications for Cell Function and Lessons Learned From Photoreceptors and Platelets. J Exp Biol 1 December 1997; 200 (23): 2927–2936. doi: https://doi.org/10.1242/jeb.200.23.2927

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Photoreceptor rod cells and blood platelets are remarkably different, yet both illustrate a similar phenomenon. Both are strongly affected by membrane cholesterol, and the distribution of cholesterol in the membranes of both cell types is determined by the lipid composition within the membranes. In rod cells, cholesterol strongly inhibits rhodopsin activity. The relatively higher level of cholesterol in the plasma membrane serves to inhibit, and thereby conserve, the activity of rhodopsin, which becomes fully active in the low-cholesterol environment of the disk membranes of these same cells. This physiologically important partitioning of cholesterol between disk membranes and plasma membranes occurs because the disk membranes are enriched with phosphatidylethanolamine, thus providing a thermodynamically unfavorable environment for the sterol. Cholesterol enrichment of platelets renders these cells more responsive to stimuli of aggregation. Stimuli for platelet aggregation cause a rapid transbilayer movement of cholesterol from the outer monolayer. This stimulus-dependent redistribution of cholesterol appears to result from the concomitant movement of phosphatidylethanolamine into the outer monolayer. The attractive, yet still unproven, hypothesis is that cholesterol translocation plays an important role in the overall platelet response and is intimately related to the sensitizing actions of cholesterol on these cells.

With remarkable foresight, Davson and Danielli (1952) clearly articulated the importance of cell membranes: ‘It can truely be said of living cells, that by their membranes ye shall know them’. Cell membranes were known then to be composed of lipids and proteins: lipids making membranes nearly impermeable to most water-soluble solutes; proteins serving as transporters and signaling devices. The classic deductions of Gorter and Grendel (1925) became the dogma that membrane lipids are arranged in a bilayer configuration: parallel sheets of phospholipids with polar or charged head groups oriented towards the aqueous environment and acyl chains interacting within the hydrophobic membrane core. The acceptance of the idea that cell membranes were not merely static barriers containing immobile proteins but dynamic lipid–protein matrices contributing to the regulation of cell function can be attributed to publication of the fluid mosaic model of cell membranes ( Singer and Nicolson, 1972 ). This model viewed membrane lipids as a viscous matrix in which transmembrane proteins have a degree of motion which, in turn, can have a dramatic impact upon protein activity. The characteristics of the lipid matrix depend upon the physical properties of the individual lipid components in the membrane.

Membrane protein activity is influenced by the surrounding lipid matrix and specifically by the association between lipids and proteins at the lipid–protein interface. At any instant, a population of lipids is always associated with a membrane protein. Depending on the time these lipids spend associated with the protein, they are classified as either restricted or interfacial lipids. Lipids that have a long residence time on the protein and exchange with lipids in the surrounding membrane at a slow rate are termed motionally restricted. The nature of the association between this group of lipids and proteins and the type of lipid that has access to the protein in this restricted domain modulates the activity of the protein. Several examples of membrane proteins that are influenced by specific restricted lipids are presented in Table 1 . In some of these cases, protein activity is subject to additional modulation by a second class of lipids, the interfacial lipids.

Examples of membrane proteins that are influenced by specific restricted lipids

Examples of membrane proteins that are influenced by specific restricted lipids

Membrane proteins may also have associated with them a sufficient number of specific or non-specific lipids which form a coat or annulus around the circumference of the protein. Such interfacial lipids exchange rapidly with the surrounding lipids and determine the bulk properties of the lipid matrix. Phosphatidylserine and stearic acid show a high affinity for contact with the transmembrane portion of the Na + /K + -ATPase, while rhodopsin requires an unsaturated fatty-acid-rich phospholipid annulus for function ( Watts et al. 1979 ). It is important to point out that, in other regions of the membrane, lipid–lipid or protein–protein interactions predominate and modulate protein function by changing the properties of the lipid–protein interface.

Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol are the constitutive lipids that provide a structural framework and the environment that defines the functional parameters associated with individual cell types. Phosphatidylcholine, phosphatidylserine and phosphatidylinositol provide for hydrated or charged membrane surfaces, allowing water and/or ions to bind to their polar headgroups. In contrast, surfaces rich in phosphatidylethanolamine are hydrophobic, poorly hydrated and promote surface-to-surface interactions without direct protein binding. Because phosphatidylethanolamine is not readily hydrated, it promotes the formation of non-bilayer structures (i.e. hexagonal II phase) to compensate for the hydrophobic effect. The inherent instability of this phospholipid is necessary in such cellular functions as membrane fusion.

Cell membranes also contain trace amounts of transient lipids, which exist in the membrane for only brief periods, serving predominantly as second messengers (for a review, see Ghosh et al. 1997 ). Phospholipids are asymmetrically distributed between the inner and outer monolayer of cell membranes (for a review, see Op den Kamp, 1979 ); choline-containing lipids, phosphatidylcholine and sphingomyelin, are found preferentially in the outer monolayer and amine-containing lipids, phosphatidylethanolamine and phosphatidylserine, are localized to the inner monolayer. The establishment and maintenance of phospholipid asymmetry occurs through a specific ATP-dependent transport protein, the aminophospholipid translocase (for a review, see Devaux, 1991 ), which translocates phosphatidylethanolamine and phosphatidylserine between the monolayers.

After phospholipids, cholesterol is the next most abundant constitutive lipid. The planar sterol ring and the hydrophobic tail orient cholesterol within the membrane core, while the 3-β-hydroxyl group allows cholesterol to contribute to the surface properties of the bilayer. The structure of cholesterol allows it to reduce the freedom of movement of phospholipid acyl chains, thus rigidifying the membrane, which can have a dramatic impact upon membrane function. This phenomenon is referred to as a ‘condensing effect’ ( Demel et al. 1972 ). The importance of the contribution of cholesterol to membrane properties is reflected in its ubiquitous distribution and its necessity for normal cell growth and function. However, high levels of membrane cholesterol, often secondary to high levels of serum cholesterol, exert deleterious effects on cells.

Like phospholipids, cholesterol is also distributed non-uniformly in cell membranes ( Dawidowicz, 1987 ; Boesze-Battaglia et al. 1996 ; Lange, 1992 ). An extreme example of non-uniform cholesterol distribution is in platelet membranes which, it is suggested, contain regions devoid of cholesterol (i.e. ‘cholesterol-free patches’) ( Gordon et al. 1983 ). Sterol carrier proteins have been identified that deliver sterol to the plasma membrane from the endoplasmic reticulum (for a review, see Schroeder et al. 1996 ), but there is no compelling evidence for a role of these proteins in transmembrane cholesterol distribution; similarly, an intramembrane cholesterol-specific translocase has not been identified.

With the acceptance of the fluid mosaic model, the concept of ‘membrane dynamics’ added a new dimension to the consideration of the functional regulation of proteins. For the purposes of this review, membrane dynamics is defined as the culmination of the motions of individual membrane components and their interrelationships in non-repeating units of the membrane. The distribution of lipids within the lateral and transverse planes of the bilayer adds another dimension to the dynamic environment of the membrane. The asymmetric bilateral organization of lipids differing in the polarity, size, charge and reactivity of their polar headgroups suggests different chemical and different dynamic environments within the two monolayers. Such differences between the two monolayers open the possibility of differential regulation of transmembrane protein activity on either side of the cell membrane. This review selects two cell types, platelets and photoreceptor cells, which provide unique model systems illustrating how changes in membrane lipid composition and membrane dynamics alter cell function. The lipid composition and distribution within the membrane of these cells can be altered, in the case of platelets quite rapidly following cell stimulation, and these lipid alterations exert control over cell function.

The plasma membrane of platelets has a lipid composition similar to that of other cells ( Lagarde et al. 1982 ; Fauvel et al. 1986 ). Phosphatidylcholine and phosphatidylethanolamine are the most abundant glycerophospholipids, each accounting for nearly 35 % of the phospholipid mass. Phosphatidylserine is less abundant, accounting for approximately 13 %, and phosphatidylinositol accounts for less than 5 %. The sphingolipid sphingomyelin contributes approximately 20 % of the lipid mass. Phosphatidylcholine and sphingomyelin are found preferentially in the outer monolayer, while phosphatidylserine and phosphatidylethanolamine are found in the inner monolayer. Platelet membranes also contain cholesterol, and the molar ratio of cholesterol to phospholipid varies, with a mean value of approximately 0.50 ( Marcus et al. 1969 ; Shattil et al. 1975 , 1977 ). The platelet membrane cholesterol concentration usually reflects the plasma cholesterol concentration and is substantially higher in hypercholesterolemic individuals ( Carvalho et al. 1974 ; Shattil et al. 1977 ). Platelets are incapable of synthesizing cholesterol, and the content and localization of the sterol in platelet membranes is probably established during their formation from megakaryocytes ( Schick and Schick, 1985 ). Platelets may also acquire cholesterol through exchange with plasma lipoproteins ( Schick and Schick, 1985 ; Aviram and Brook, 1980 ).

Platelet membranes demonstrate a unique phenomenon: upon exposure to stimuli of aggregation, membrane phospholipids move rapidly between the two monolayers and the asymmetric distribution of phospholipids in the platelet plasma membrane is disrupted (for reviews, see Schroit and Zwaal, 1991 ; Zwaal and Schroit, 1997 ). The seminal observation supporting this proposal is that phosphatidylethanolamine and phosphatidylserine are poorly hydrolyzed by exogenous phospholipase A 2 except when platelets are exposed to collagen, thrombin or ionomycin, which greatly increase the rate of hydrolysis of these lipids by phospholipase A 2 ( Bevers et al. 1982 , 1983 ). Schick et al. (1976) showed that 2,4,6-trinitrobenzenesulfonic acid reacted with a much greater percentage of the phosphatidylethanolamine following incubation with thrombin. They proposed that phosphatidylethanolamine is rapidly translocated from the inner to the outer monolayer upon stimulation. More contemporary studies incorporated either fluorescent ( Gaffet et al. 1995 ; Smeets et al. 1994 ; Tilly et al. 1990 ; Williamson et al. 1995 ) or spin-labeled ( Basse et al. 1993 ; Sune et al. 1987 ) phospholipid probes into platelet membranes. Stimulation of platelets caused these probes to translocate from one monolayer to the other and, on this basis, investigators inferred that the distribution of endogenous membrane lipids changed in a qualitatively similar manner. The disruption of phospholipid asymmetry in the platelet plasma membrane may involve a bidirectional movement of phospholipids between the membrane monolayers, a so-called scrambling of lipids ( Smeets et al. 1994 ; Williamson et al. 1995 ). Alternatively, Gaffet et al. (1995) proposed a vectorial efflux of phosphatidylserine and phosphatidylethanolamine from the inner to the outer monolayer without an accompanying reciprocal influx of choline phospholipids. The loss of phospholipid asymmetry is not the result of inhibition of the aminophospholipid translocase activity ( Basse et al. 1993 ; Comfurius et al. 1990 ), and investigators have proposed that a separate enzyme activity, termed a scramblase ( Zwaal and Schroit, 1997 ), catalyzes the transmembrane redistribution of phospholipids in platelets. Similar evidence has been presented for erythrocytes ( Smeets et al. 1994 ). This putative activity appears to be activated in response to the elevation of intracellular [Ca 2+ ] ( Williamson et al. 1992 ; Dachary-Prigent et al. 1995 ; Smeets et al. 1994 ; Zwaal and Schroit, 1997 ), which simultaneously inhibits the aminophospholipid translocase ( Comfurius et al. 1990 ). Persuasive evidence supporting the presence of a scramblase in platelet membranes was recently provided by Comfurius et al. (1996) . These investigators reconstituted a platelet membrane protein preparation into lipid vesicles containing 7-nitrobenz-2-oxa-1.3-diazol-4-yl (NBD)-labeled phospholipids. The addition of Ca 2+ and a Ca 2+ ionophore to the vesicles induced the transbilayer movement of the NBD-labeled phospholipids. Efforts to purify and further characterize the protein(s) responsible for this enzyme activity have not yet been reported.

Work in our laboratory has added an additional component to the stimulus-dependent rearrangement of membrane lipids in platelets. We have documented a translocation of cholesterol from the outer to the inner monolayer coincident with phosphatidylethanolamine translocation to the outer monolayer ( Boesze-Battaglia et al. 1996 ). The mechanisms underlying this stimulus-dependent translocation of cholesterol are not understood. Evidence suggests that the translocation of cholesterol may be linked to the concomitant translocation of phosphatidylethanolamine through a protein-independent process (i.e. a thermodynamic process). Model membrane ( Yeagle and Young, 1986 ; Backer and Dawidowicz, 1981 ) and biological membrane ( House et al. 1989 ) studies have found that the introduction of phosphatidylethanolamine into membranes creates a thermodynamically unfavorable environment for cholesterol. The thermodynamic constraints when cholesterol and phosphatidylethanolamine coexist predict an unfavorable entropy, causing the translocation of cholesterol from the phosphatidylethanolamine-rich lipid environment as a compensatory mechanism. It is proposed that such partitioning of cholesterol is due to the increased ordering of water molecules on the membrane surface. Chaotropic agents relieve the constraint on the membrane by disrupting the interstitial hydrogen-bonded water and, thereby, allow both lipids to coexist within the same bilayer. In fact, cholesterol translocation is blocked by exposure of platelets to the chaotropic agents urea and guanidine–HCl ( Boesze-Battaglia et al. 1996 ). However, the participation of an enzymatic activity in cholesterol translocation has not been investigated.

Platelet responses culminating in aggregation are strongly influenced by the cholesterol content of the platelet membrane and are positively correlated with the membrane cholesterol content. Carvalho et al. (1974) reported increased sensitivity to epinephrine, ADP- and collagen-initiated aggregation and increased nucleotide release in platelets from patients with hypercholesterolemia. Supporting the view that the increased sensitivity of platelets removed from hypercholesterolemic individuals is a consequence of their elevated cholesterol levels are data from studies by Shattil et al. (1975) and Tomizuka et al. (1990) reporting increased sensitivity of platelets to epinephrine, ADP and thromboxane A 2 when the platelets had been enriched with cholesterol in vitro. Shattil et al. (1975) also reported a reduction of platelet sensitivity to epinephrine following the loss of platelet cholesterol. A related study noted that hypercholesterolemia was associated with an increased number of lower-density platelets, which were more responsive to thrombin stimulation ( Opper et al. 1995 ).

The mechanisms underlying cholesterol modulation of platelet function are not well established. A number of signal transduction events have been shown to be increased following cholesterol enrichment of platelets. These events include increased release of arachidonic acid, indicative of phospholipase A 2 activity ( Sorisky et al. 1990 ; Stuart et al. 1980 ), increased adrenergic and thrombin receptor numbers ( Insel et al. 1978 ; Tandon et al. 1983 ), and higher receptor-stimulated Ca 2+ and inositol phosphate levels ( Sorisky et al. 1990 ). While cholesterol may be acting as a restricted lipid directly modifying the function of integral membrane proteins mediating signal transduction events, anisotropy and polarization data suggest that cholesterol behaves like an interfacial lipid modulating the bulk properties of the bilayer. In this regard, Shattil and Cooper (1976) reported an increased viscosity of platelet membranes upon enrichment with cholesterol, and this fundamental relationship has been confirmed by others in platelets ( Hochgraf et al. 1994 ). Alternatively, the mechanism of cholesterol action may be related to cholesterol-induced changes in membrane thickness ( Chen et al. 1995 ).

The rapid reorganization of membrane lipids, including cholesterol, in platelets makes it likely that the dynamic properties of platelet membranes change as a result of stimulation. The bulk properties of membranes can be assessed using fluorescence polarization and anisotropy measurements, which reveal the mean angular displacement of a fluorophore that occurs between the absorption and subsequent emission of a photon. This angular displacement is dependent on the rate and extent of rotational diffusion during the lifetime of the excited state. These diffusive motions in turn depend on the viscosity of the solvent, in this case the lipid bilayer. The often-used term for this property of the lipid bilayer is ‘fluidity’. The higher the polarization or anisotropy value, the lower the membrane fluidity and the more ordered the membrane.

A number of studies employing fluorescent membrane probes have reported decreases in platelet membrane fluidity following platelet stimulation. Nathan et al. (1979) reported an increase in 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence polarization coincident with shape change and aggregation in thrombin-or ADP-stimulated platelets and concluded that platelet activation is accompanied by an increased rigidity of the membrane lipids. Steiner and Luscher (1984) and Kowalska and Cierniewski (1983) reported similar findings using 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS) or DPH, respectively, in platelets stimulated with thrombin, ADP or fibrinogen. Steiner and Luscher (1984) detected a decrease in anisotropy which preceded the rise in anisotropy of thrombin-stimulated but not ADP-stimulated platelets. The increase in anisotropy in response to thrombin could be prevented by pretreatment with cytochalasin B, suggesting a role of the extensive platelet cytoskeleton in thrombin-induced changes in anisotropy. Nathan et al. (1980) subsequently reported similar findings using N -carboxymethylisatoic anhydride, a fluorescent probe which binds covalently to membrane proteins. The similar changes in polarization using the two probes suggested that the changes in the microenvironment surrounding the membrane proteins are analogous to the changes in the overall dynamic properties of the bulk membrane lipids. Taken together, these findings suggest an increased ordering of platelet membrane lipids following stimulation.

The molecular mechanisms underlying the changes in platelet membrane dynamics following stimulation are not known but, given the profound influence of cholesterol on membrane fluidity ( Shattil et al. 1975 ), it is possible that the intramembrane redistribution of cholesterol ( Boesze-Battaglia et al. 1996 ) underlies some of the reported changes in platelet membrane fluidity. Extending this reasoning leads to the view that the dynamic properties of the inner and outer monolayer may not change in concert with one another, as is the case with unstimulated fibroblasts ( Schroeder, 1978 ). Thus, given the rearrangement of phospholipids and cholesterol upon stimulation, the relative dynamic properties of the two monolayers must be determined independently. Future investigations into platelet membrane function should include efforts to resolve the relative changes in fluidity of each monolayer of the membrane.

Although the unique rearrangement of membrane lipids in stimulated platelets has been appreciated for two decades, its significance in terms of platelet responses leading to aggregation has eluded investigators. However, another role has been ascribed to stimulus-dependent phospholipid reorganization: in addition to promoting aggregation, platelet activation also alters the platelet membrane to provide a catalytic surface for the conversion of factor X to factor Xa and of prothrombin to thrombin, which then catalyzes fibrinogen formation. The formation of this catalytic surface requires exposure of the anionic phospholipid phosphatidylserine ( Bevers et al. 1982 ). Patients with Scott syndrome, a rare bleeding disorder ( Weiss et al. 1979 ), have an isolated deficiency in the formation of a platelet procoagulant activity due to a failure to expose phosphatidylserine on the outer membrane monolayer ( Bevers et al. 1992 ; Sims et al. 1989 ). Platelets from patients with Scott syndrome exhibit apparently normal aggregation in response to stimuli and have a lipid composition indistinguishable from that of normal platelets. Erythrocytes from patients with Scott syndrome have a similar defect ( Bevers et al. 1992 ). The molecular basis for Scott syndrome is not known, but the possibility that platelets and erythrocytes from these patients are deficient in the putative ‘scrambalase’ enzyme has been excluded ( Stout et al. 1997 ).

Photoreceptor rod cells provide a unique window in which the relationship between physiological function and membrane lipid composition may be visualized. These cells convert light energy into a change in electrical potential, triggering a nerve impulse that is ultimately delivered to the visual cortex. The biochemical events initiating this process occur within the disk membranes located in the interior of the rod outer segment (ROS, Fig. 1 ). The disks are closed, flattened membranous sacs organized in a discontinuous stacked array along the length of the outer segment. Nascent disks are formed from evaginations of the surrounding ROS plasma membrane at the base of the cell and are then progressively displaced towards the apical tip of the outer segment as additional new disks are formed. Old disks are shed at the apical tip and phagocytosed by the overlying retinal pigment epithelium. The transition of disks from the base to the tip of the outer segment requires approximately 10 days in mammals and maintains the ROS at a constant length.

Schematic representation of a retinal rod cell.

Schematic representation of a retinal rod cell.

Disks and plasma membranes differ in their lipid composition ( Table 2 ). The plasma membrane is enriched in cholesterol ( Boesze-Battaglia and Albert, 1989 ) and the sterol precursor squalene ( Fliesler et al. 1997 ) relative to the disk membrane. In plasma membrane, the ratio of phosphatidylethanolamine to phosphatidylcholine is 0.16, while in disks this ratio is 0.92 ( Boesze-Battaglia and Albert, 1992 ) ( Table 2 ). The fatty acid composition ( Boesze-Battaglia et al. 1989 ) and the ratio of saturated to unsaturated fatty acids is also markedly different ( Lamba et al. 1994 ) ( Table 3 ). The most prominent difference is in docosahexaenoic acid (DHA, 22:6), which accounts for 5 % of the total in plasma membrane but 35 % in disk membrane. Collectively, these findings suggest a tremendous sorting of lipid constituents at the base of the ROS upon disk biogenesis.

Cholesterol and phospholipid headgroup composition of rod outer segment membranes

Cholesterol and phospholipid headgroup composition of rod outer segment membranes

Fatty acid composition of rod outer segment membranes

Fatty acid composition of rod outer segment membranes

As the disk membranes are apically displaced, their cholesterol content decreases from 30 mol % at the base of the ROS to 5 mol % at the apical tip ( Boesze-Battaglia et al. 1989 , 1990 ). There is no corresponding change in fatty acid or phospholipid composition among disks at different locations in the ROS. The loss of cholesterol as the disk membranes age can be explained by a cholesterol-partitioning model similar to that invoked to account for translocation of cholesterol in collagen-stimulated platelets. In disks, it is proposed that cholesterol is exchanged out of the phosphatidylethanolamine-rich disk membrane into the phosphatidylcholine-rich plasma membrane. Thus, on the basis of the relative differences in the phosphatidylethanolamine/phosphatidylcholine ratio between the disk and the plasma membranes, a gradient is formed which favors the movement of cholesterol from the disk membrane to the plasma membrane during the lifetime of a disk ( Yeagle and Young, 1986 ; House et al. 1989 ).

Aberrant lipid sorting between disk and plasma membranes is associated with disease states, as illustrated by the Royal College of Surgeons (RCS) strain of rats. These rats carry a recessive mutation which results in a degeneration of the retinal photoreceptor cells ( Dowling and Sidman, 1962 ; Noell, 1965 ). The rhodopsin content ( Organisciak et al. 1982 ) and the glycosylation pattern ( Endo et al. 1996 ) of this protein are similar in both the normal and diseased animals. One characteristic of this disease is an apparent absence of lipid sorting during disk biogenesis ( Boesze-Battaglia et al. 1994 ). As a result, the plasma membrane phospholipid composition is virtually identical to that of the disk membranes. It is hypothesized that, in the absence of a phosphatidylethanolamine/phosphatidylcholine gradient between the disk and plasma membranes of the RCS rat, there is no partitioning of the cholesterol and, in fact, disk membrane cholesterol level in the RCS rat remains constant at 15 mol % as a function of disk age. The photoreceptors of these animals exhibit abnormal growth, leading to the accumulation of membrane debris and ultimately to blindness, thus providing compelling evidence of the need for the photoreceptor membranes to maintain their distinct lipid composition for normal cell function.

The light sensor, rhodopsin, initiates the visual response as a transmembrane protein in a disk lipid matrix. The sequence of intracellular events triggered by rhodopsin activation has been extensively characterized (for a review, see Stryer, 1986 ) and is analogous to the β-adrenergic receptor-dependent activation of adenylate cyclase ( Oprian, 1992 ). The absorption of a photon of light results in the photoisomerization of 11- cis retinal, the retinal chromophore of rhodopsin, to all- trans retinal, leading to a series of conformational changes necessary for the formation of Metarhodopsin II, the activated form of rhodopsin ( Bennet et al. 1982 ). The coupling of the photoreceptor G-protein transducin with activated rhodopsin (Metarhodopsin II) facilitates the activation of the cyclic-GMP-dependent phosphodiesterase. Because rhodopsin is the predominant protein in the disk membrane (95 % of total protein; Papermaster and Dreyer, 1972 ) and the surrounding plasma membrane (80–85 % of total protein; Molday and Molday, 1987 ), studies directed towards investigating rhodopsin function in two compositionally distinct membranes from the same cell are possible.

Rhodopsin activation of the cyclic-GMP-dependent phosphodiesterase (PDEase) differs in disk and plasma membrane preparations ( Boesze-Battaglia and Albert, 1990 ). As shown in Fig. 2 , plasma membrane rhodopsin requires a light intensity at least two orders of magnitude greater than disk membrane rhodopsin to achieve the same maximal PDEase activity. Because of the profound influence of cholesterol upon the acetycholine receptor ( Criado et al. 1982 ; Dreger et al. 1997 ) and the Na + /K + -ATPase ( Yeagle et al. 1988 ), and since the plasma membrane contains three times more cholesterol than the disks, we investigated the effect of cholesterol on rhodopsin activation of PDEase. When the cholesterol content of ROS plasma membranes preparations was reduced by incubation with cholesterol oxidase, the PDEase activity was restored, suggesting that the high cholesterol content of these membranes inhibits the activation of phosphodiesterase by rhodopsin.

Phosphodiesterase (PDEase) activity of cholesterol-oxidase-treated plasma membrane. PDEase stimulus–response curves for disk membrane (♦), for plasma membrane (◊) and for cholesterol-oxidase-treated plasma membrane (+). PDEase activity is expressed as a percentage of the maximal activity. The plasma membrane was treated with cholesterol oxidase as described in Boesze-Battaglia and Albert (1990). Both the disk preparation and the untreated plasma membrane preparation were incubated at 37 °C. The results shown represent two independent preparations. RL, room light. Taken from Boesze-Battaglia and Albert (1990) with permission.

Phosphodiesterase (PDEase) activity of cholesterol-oxidase-treated plasma membrane. PDEase stimulus–response curves for disk membrane (♦), for plasma membrane (◊) and for cholesterol-oxidase-treated plasma membrane (+). PDEase activity is expressed as a percentage of the maximal activity. The plasma membrane was treated with cholesterol oxidase as described in Boesze-Battaglia and Albert (1990) . Both the disk preparation and the untreated plasma membrane preparation were incubated at 37 °C. The results shown represent two independent preparations. RL, room light. Taken from Boesze-Battaglia and Albert (1990) with permission.

The molecular mechanism by which cholesterol modulates PDEase activity through the formation of Metarhodopsin II has been extensively characterized. In a series of elegant reconstitution experiments, Litman and his colleagues demonstrated that increasing membrane cholesterol level shifts the equilibrium between Metarhodopsin I and Metarhodopsin II ( Straume and Litman, 1987 , 1988 ; Mitchell et al. 1990 ) towards Metarhodopsin I. Thus, Metarhodopsin II formation is inhibited in the presence of high levels of membrane cholesterol. Cholesterol exerts this effect by modulating the ‘free volume’ of the bilayer. The unsaturated acyl chains of the phospholipids assume a cis / trans conformation, which produces ‘kinks’ in the membrane bilayer. Such kinks take up space or, in three dimensions, ‘volume’, allowing for transient packing defects within the bilayer. These small volume defects are decreased in the presence of cholesterol, thereby inhibiting Metarhodopsin II formation since Metarhodopsin II requires volume expansion by the protein. This series of studies provides compelling support for the modulation of rhodopsin function through changes in the bulk dynamic properties of the ROS membrane bilayer.

In a recent series of experiments, Albert et al. (1996 a , b ) suggested that cholesterol stabilizes and interacts directly with rhodopsin. Using the fluorescent sterol probe cholestatrienol and fluorescence energy transfer techniques, they proposed a direct interaction between cholesterol and rhodopsin (Albert et al. 1996 b ). This conclusion is supported by an analysis of spin-labeling experiments, which suggest that a non-phospholipid moiety, probably cholesterol, is found at the lipid–protein interface ( Watts et al. 1979 ). Rhodopsin is thus modulated not only by the bulk membrane properties of the disks (i.e. through changes in free volume) but also potentially through a direct interaction with cholesterol. Additional experiments are needed to determine the mechanism by which cholesterol acting as a restricted lipid modulates rhodopsin function.

After bleaching, the apo-protein opsin recombines with 11- cis retinal to form newly activatable rhodopsin. Evidence has accumulated over the last decade implicating DHA in rhodopsin regeneration. DHA or its precursor (18:3 n -3) must be furnished in the diet ( Tinoco, 1982 ; Scott and Bazan, 1989 ). In animal models, deprivation of these fatty acids for two generations results in a loss of visual function ( Benolken et al. 1973 ; Wheeler et al. 1975 ; Dudley et al. 1975 ) and ROS disk disruptions ( Futterman et al. 1971 ; Bush et al. 1991 ). Bush et al. (1994) have shown that rats with decreased levels of DHA showed a slower rate of rhodopsin regeneration compared with controls. Interestingly, plasma membrane rhodopsin does not regenerate to the same extent as disk membrane rhodopsin ( Table 4 ). In fact, the plasma membrane contains only 5 % DHA while the disk membrane contains 35 %. Given that DHA is the predominant fatty acid on phosphatidylethanolamine and that rhodopsin maintains a phospholipid annulus whose composition has not been determined, it is tempting to speculate that the differences in rhodopsin regeneration are due to differences in the phosphatidylethanolamine composition of the lipid annulus of rhodopsin.

Opsin regeneration in rod outer segment membranes

Opsin regeneration in rod outer segment membranes

By utilizing different lipid components to regulate various aspects of rhodopsin function in conjunction with cytoplasmic components such as kinases, photoreceptors provide for various levels of functional control. The need for such complexity in this regulation can be appreciated if one considers the range of light intensities to which rhodopsin must respond both continuously and intermittently. To conserve rhodopsin function, and hence photoreceptor function, rhodopsin is maintained in a relatively inactive state in the plasma membrane. In this membrane, there is a high level of cholesterol (thus rhodopsin activation is inhibited) and low levels of DHA (thus rhodopsin regeneration occurs slowly). Upon entering the lower-cholesterol, higher-DHA environment of the disk through disk biogenesis, inhibition is removed. Thus, it can be said that the plasma membrane lipid environment may ‘protect’ rhodopsin from bleaching by light, thereby allowing for the maximal amount of activatable rhodopsin to be incorporated into newly formed disks.

The molecular mechanism by which DHA maintains visual function can be explained if one considers how changes in this lipid affect free volume. The presence of cis double bonds in unsaturated fatty acids will increase free volume by introducing ‘kinks’ within the membrane bilayer. DHA contributes as many as six cis bonds. It can be hypothesized that, as the cholesterol/DHA ratio in the disk membranes decreases as the disk ages, a lipid environment is established that favors Metarhodopsin II formation (and therefore favors rhodopsin activation of PDEase) and the subsequent regeneration of rhodopsin (high DHA levels) for continual activation. In fact, Metarhodopsin II formation is favored in the presence of unsaturated fatty acids ( Mitchell et al. 1992 ) such as DHA. The delicate balance between a molecule that enhances free volume (DHA) and one that restricts free volume (cholesterol) allows the photoreceptor to function under what may seem to be adverse light conditions. In general, the larger free volume component associated with the disks as they age contributes to the effective overall functioning of the ROS as a transducer of light.

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Lipids: Composition, structure, and function

by Nathan H Lents, Ph.D., Lizzie Stark, M.S./M.F.A, Bonnie Denmark, M.A./M.S.

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Did you know that studying lipids can help us understand and treat medical conditions such as heart disease, hormone disorders, multiple sclerosis, and many others? Lipids are necessary for the structure of all living cells. Their chemical composition allows them to have many important functions, from storing energy to regulating metabolism to helping the fur coat of sea otters repel water.

Lipids are a large and diverse class of biological molecules marked by their being hydrophobic, or unable to dissolve in water.

The hydrophobic nature of lipids stems from the many nonpolar covalent bonds. Water, on the other hand, has polar covalent bonds and mixes well only with other polar or charged compounds.

Fats and oils are high-energy molecules used by organisms to store and transfer chemical energy. The distinct structures of different fat molecules gives them different properties.

Phospholipids are specialized lipids that are partially soluble in water. This dual nature allows them to form structures called membranes which surround all living cells.

What do butter, beeswax, and testosterone have in common? They’re all lipids , a type of compound produced by plants and animals that includes fats and oils as well as waxes and steroids. As a group, lipids have many different functions and uses in living cells and organisms , from storing energy to regulating metabolism , signaling hormones , and providing the structure of cell membranes . They help sea otters’ fur repel water and give a waxy sheen to many plant leaves. In our daily lives, lipids provide the delicious richness in ice cream, give carrots their color, lubricate our car engines, and help clean our clothes.

  • What is a lipid?

If you have ever made salad dressing, seen a photograph of an oil tanker spill, or tried to clean a greasy stain with water, then you have likely noticed one of the defining factors of lipids: They do not mix well with water. Lipids are mainly composed of carbon and hydrogen atoms , and this hydrophobic ("water fearing") nature of lipids is driven by the bonds between these many carbons and hydrogens.

In a water molecule , the bonding between the oxygen and hydrogen atoms results in a polar covalent bond (see our module Water: Properties and Behavior ). The electrons that form this bond are shared unequally between the atoms because oxygen atoms have a stronger pull on electrons than hydrogen does. This creates a slight negative charge at the oxygen end of the water molecule, and a slight positive charge at the hydrogen end, as shown in Figure 1.

Water molecule

However, the bonding between carbon and hydrogen atoms in lipids is not polar . This is because the electrons in the covalent bonds are shared equally between the carbons and the hydrogens and there are no partial charges anywhere. Thus, long chains of carbon-hydrogens bonds form a nonpolar molecule .

The bonding differences between water and lipid molecules is important because “like attracts like.” As a polar solvent , water prefers to dissolve molecules with polar bonds , such as salt and sugar . Molecules with nonpolar bonds will not normally dissolve in polar solvents because there is no charge on the nonpolar molecule to attract the polar molecule . Nonpolar liquids mix with other nonpolar liquids and dissolve nonpolar solutes (the substance that is dissolved); polar liquids mix with other polar liquids and dissolve polar or charged solutes.

While lipids cannot dissolve in polar solvents , they can dissolve in nonpolar solvents – those with a balanced electron distribution – such as gasoline and chloroform. This is why lighter fluid can help remove engine grease and cooking oil stains from clothing.

Comprehension Checkpoint

  • Lipid compounds

As a group, lipids are a diverse collection of naturally-occurring organic compounds with important roles to play:

  • Fats and oils store energy for cells . In animals, they provide electrical insulation for nerves, and cushion internal organs.
  • Phospholipids form cellular membranes and play an important role in diffusion (see our Membranes I: Introduction to Biological Membranes module).
  • Steroids are formed from cholesterol and are involved in cellular communication.
  • Carotenoids are pigments used to help absorb light energy in plants, algae , and photosynthetic bacteria .
  • Waxes form a barrier to exclude water in both plants and animals. Waxes are found in leaves, ear canals, and the beeswax that makes honeycomb.
  • The composition of lipids

Without fully realizing it, humans have been performing chemical reactions with lipids for thousands of years. Soap, for example, was a very early human invention and possibly the first such innovation to be the result of a chemical reaction . There is even a recipe for making soap on Sumerian tablets dating back to 2500 BCE (Levey, 1954). In the ancient world, soap was made by first boiling rainwater with ashes from burnt wood to produce lye: a very basic, or alkaline, solution (high pH) (see our Acids and Bases: An Introduction module). Next, this solution was combined with animal fat or vegetable oil and cooked over a low fire for many hours until the mixture changed into a gel. The fundamental procedure of this chemical reaction, now called saponification , is still used today to make soap.

The first steps toward understanding lipids were taken in the early 1800s by a young French scientist named Michel Chevreul (1786-1889). Chevreul began his career in the laboratory of Louis Vauquelin, where his role was to use various solvents (such as water, alcohol , and ether) to separate the colored dye pigments from natural products like vegetable oils, waxes, tree gums, and resins. Without knowing it, he was working with various kinds of lipids (McNamara, Warnick, & Cooper, 2006).

At the end of each experiment , Chevreul would wash out the glassware using a lot of soap. While conducting his research , Chevreul observed that if he accidentally left soapy water in some glassware and it evaporated overnight, salt crystals would be left behind. He was confused by this because he had added only water (or another solvent) and soap to the glassware. It raised the question: Where was the salt coming from? Through deductive reasoning, Chevreul realized it must be the result of the soap. When he learned how soap was made by mixing animal or vegetable fat with alkali water, though, he was still confused because there was no salt in that process either.

Intrigued and persistent, Chevreul went on to study the process of soap-making in his own laboratory. As he made various kinds of soap, he observed that as oils react with the alkali water, they turn from a translucent liquid into a thick, milky pudding, which gradually hardens. At the time, he knew that oils and fats contain large amounts of carbon and hydrogen and only small amounts of oxygen. He hypothesized that the reaction with the alkali solution , which had a high pH and thus a higher concentration of hydroxide ions (OH - ), was somehow adding oxygen atoms to the structure of the fats to change them from pure hydrocarbons to molecules with some salt-like properties.

This was an excellent hypothesis because it would explain two different phenomena at the same time. First, it explained the salt crystals left when soapy water dries. Second, it explained why soap is soluble in both water and oil. The hydrocarbons from the fat would still be oil-soluble, but their new salt-like properties, coming from the added oxygen atoms , would allow them to be soluble in water, a property that all salts have.

  • The structure of fats

Although it took him most of his career to do it, Chevreul demonstrated that his hypothesis was correct. He did this by performing painstaking chemical analyses of various fats, oils, and the soaps that are produced when alkali is added to them. Chevreul discovered that, during saponification , some of the hydroxide (OH - ) ions from the alkali solution are indeed added to the hydrocarbons from the fats. When this happens, some chemical bonds in the fat molecules are broken, releasing long-tailed fatty acids (Figure 2). Many of the names of common fatty acids that we use today were given to these molecules by Chevreul (Cistola et al. , 1986).

Figure 2: The basic chemical reaction of saponification.

Figure 2 : The basic chemical reaction of saponification.

The reason that hydrocarbon tails from fats are not soluble in water is because almost all of the bonds are symmetrical and thus nonpolar. However, when the hydroxide ions break the ester group in fat molecules during saponification , a charged and polar group is created – a carboxylic acid group – which is very soluble in water.

These fatty acids have a very special structure. They have long chains of nonpolar bonds , which makes them easily dissolvable in oil and grease; but they also have a polar charged group at one end, which makes them easily dissolvable in water. Thus, these molecules have a dual nature – they are both water-soluble (hydrophilic, "loves water") and oil-soluble (lipophilic, "loves fat"). The word for this is amphiphilic , which means "loves both." This is why fatty acids perform so well as soaps and detergents – they are capable of dissolving, and thus cleaning, both watery and greasy substances.

What Chevreul and others showed was that an alkali solution breaks up the fat molecules and two parts are released: glycerol and fatty acids . We now know the complete structure of the fat molecule (Figure 3).

Figure 3 : A fat molecule showing its component parts: the glycerol, carboxyl groups, and fatty acids. From Harrigan, G.G., Maguire, G., and Boros, L. 2008. Metabolomics in alcohol research and drug development. Alcohol research Health, 31 (1): 27-35.

During the process of saponification , the hydroxide ions in the alkali solution "attack" the ester group and thus release the fatty acid chains from the glycerol backbone. Chevreul was able to figure this out by analyzing the chemical composition of the fats before the reaction , and then repeating the analysis with the fatty acids that resulted. He did this again and again with different kinds of fats, which made slightly different kinds of soaps. The result was the common theme that fats are made of glycerol and fatty acids.

  • Fats and oils store energy

Animals and plants use fats and oils to store energy . As a general rule, fats come from animals and oils come from plants. Because of slight differences in structure, fats are solid at room temperature and oils are liquid at room temperature. However, both fats and oils are called triglycerides because they have three fatty acid chains attached to a glycerol molecule , as shown in Figure 3.

The carbon-hydrogen bonds (abbreviated C-H) found in the long tails of fatty acids are high-energy bonds. Thus, triglycerides make excellent storage forms of energy because they pack many high-energy C-H bonds into a compact structure of three tightly packed fatty acid tails. For this reason, dietary fats and oils are considered "calorie dense ." When animals, including humans, consume fats and oils, a relatively small volume can deliver a large number of calories. Animals, particularly carnivores, are drawn to high-fat foods for their high caloric content.

Triglycerides are formed inside plant and animal cells by attaching fatty acids to glycerol molecules , creating an ester linkage . This reaction is called a dehydration synthesis because a water molecule is formed by "pulling out" two hydrogen atoms and an oxygen from the reactants . Because a new water molecule is formed, this new reaction is also called a condensation reaction (see Figure 4).

Figure 4: The dehydration synthesis reaction, where a water molecule is formed by

Figure 4 : The dehydration synthesis reaction, where a water molecule is formed by "pulling out" two hydrogen atoms and one oxygen atom.

  • Structure of fatty acids

The reason why fats are solid at room temperature while oils are liquid has to do with the shape of the fatty acids these triglycerides contain. Remember that the fatty acids are long chains of carbon molecules that have hydrogen atoms attached. The C-H bonds are where energy is stored. At one end of the tail, fatty acids have a carboxyl group (-COOH), which gives the molecule its acidic properties (Figure 5).

Figure 5: The essential features of a fatty acid showing the long hydrocarbon chain and the carboxylic acid group.

Figure 5 : The essential features of a fatty acid showing the long hydrocarbon chain and the carboxylic acid group.

If a fatty acid looks like the molecule above, with only single bonds between the carbons, we say that this fatty acid is saturated . This term is used because every single carbon is surrounded by as many hydrogen atoms as is possible; it is saturated with hydrogen.

However, some fatty acids have a double bond between two of the carbons in the chain. Wherever this double bond exists, abbreviated C=C, both of the carbons involved in this double bond have one less hydrogen than the other carbons. This is because carbon can only normally make four bonds. When two carbons form a second bond in between them, they each must "let go" of a hydrogen so that the total number of bonds for each carbon is still four. Because these fatty acids have two fewer hydrogen atoms than they otherwise would have, we call them unsaturated fatty acids (Figure 6). They are unsaturated because they do not contain the maximum number of hydrogen atoms that they could have.

Figure 6: A mono-unsaturated fatty acid.

Figure 6 : A mono-unsaturated fatty acid.

When a fatty acid has a double bond in its chain, the chain has a "kink" in its shape because there is no free-rotation around a C=C double bond. The kink is "fixed" in the structure of the fatty acid. In contrast, saturated fatty acids have free rotation around all of the single bonds in the chain since saturated fatty acids are long and straight. A comparison is shown in Figure 7.

The kinks found in unsaturated fatty acids make it so that many chains cannot pack together very tightly. Instead, the kinks force the fatty acids to push further apart. For this reason, triglycerides with unsaturated fatty acids are liquid at room temperature. Instead of packing together tightly, the molecules can slide past each other easily. The opposite is true for triglycerides with saturated fatty acids. Because their fatty acid tails are straight with no kinks, they can pack together very tightly. Thus, these molecules are more dense and solid at room temperature.

Figure 7: A comparison of a saturated fatty acid (stearic acid, found in butter) and an unsaturated fatty acid (linoleic acid, found in vegetable oil).

Figure 7 : A comparison of a saturated fatty acid (stearic acid, found in butter) and an unsaturated fatty acid (linoleic acid, found in vegetable oil).

Animal fats are often saturated, which explains why lard, bacon fat, and butter are all solid at room temperature. Plant triglycerides, on the other hand, are typically unsaturated. This is why vegetable oils (such as canola, olive, peanut, etc.) are liquid at room temperature. Most often, unsaturated fats have only one C=C double bond and are thus called mono unsaturated . However, some plants make triglycerides with multiple C=C bonds. These kinds of triglycerides are called poly unsaturated . (See Figure 8.)

Figure 8: A comparison of the bonds in a monounsaturated fatty acid (oleic acid) and a polyunsaturated fatty acid (linoleic acid).

Figure 8 : A comparison of the bonds in a monounsaturated fatty acid (oleic acid) and a polyunsaturated fatty acid (linoleic acid).

Monounsaturated fats appear to be the healthiest triglycerides for humans to consume in their diets because the cells that remove fats from our blood after they are absorbed from our diet do their work most quickly with monounsaturated fats. Because we are slower to remove them from our blood, saturated fats stay in our bloodstream longer and thus have a greater chance to contributing to the formation of plaques and clots. For this reason, doctors and dieticians recommend diets high in monounsaturated fats and low in saturated fats. Polyunsaturated fats are somewhere in between saturated and monounsaturated fats in terms of their healthiness in our diet (Mattson & Grundy, 1985).

Another type of fatty acid that has gotten a lot of attention recently is the trans fatty acid. Trans fatty acids have a hydrocarbon tail with a double bond that is in the trans configuration , instead of the more common cis configuration (see Figure 9).

Figure 9: A comparison of the cis double-bond configuration and the trans double-bond configuration.

Figure 9 : A comparison of the cis double-bond configuration and the trans double-bond configuration.

As discussed above, C=C double bonds are present in the fatty acid tails of unsaturated fats. When these unsaturated fatty acids are made naturally by living cells , most often plant cells, the C=C double bonds are always in the cis configuration , almost never in the trans configuration. However, during industrial production of certain fat-containing products , the trans configuration can be inadvertently formed. This occurs when unsaturated fats, usually vegetable oils, are subjected to the process of hydrogenation in order to turn them into saturated fats (shown in Figure 10).

Figure 10: Unsaturated fats, usually vegetable oils, are subjected to the process of hydrogenation in order to turn them into saturated fats.

Figure 10 : Unsaturated fats, usually vegetable oils, are subjected to the process of hydrogenation in order to turn them into saturated fats.

The purpose of industrial hydrogenation is to create solid fats, which are more desirable for deep-frying, out of vegetable oils. This is done because vegetable oils are much less expensive than naturally saturated fats such as lard. Crisco™ and margarine are two such chemically-produced saturated fats that are made of hydrogenated vegetable oils. Crisco™, or shortening, is cheaper than lard but can be used similarly and gives similar taste. Margarine, or oleo, was developed as a cheaper substitute for butter, particularly during the era of the World Wars and global depressions that marked the first half of the 20 th century, when rationing and scarcity of staples was common. Today, many packaged desserts and candies also have these kinds of industrially produced saturated fats, which often cost less than natural saturated fats but provide better texture and firmness than unsaturated fats. During hydrogenation, occasionally the chemical reaction does not go to completion and the process of turning a cis unsaturated fat into a saturated fat creates a trans fat instead.

In recent years, trans fats have received a lot of attention from dieticians and the general public because of their association with elevated health risks. Individuals with diets higher in trans fats are more likely to develop coronary heart disease, suffer heart attacks and stroke, and die earlier than those with diets low in trans fats (Mensink & Katan, 1990). It was always known that hydrogenation produces some trans fats, but because they are not acutely toxic, their long-term health dangers are only now being realized.

Scientists have discovered the reason for these elevated risks: Trans fats spend a much longer amount of time in our bloodstream after we consume them, instead of being quickly absorbed into our cells . Unlike saturated fats and cis unsaturated fats, trans fats don't appear in nature in very large amounts – they are an "unnatural" form of fat which humans are not well designed to consume. Because humans only began to eat trans fats in the 20 th century (other than the very tiny amounts that are present in some forms of red meat), we do not have receptor molecules in our blood vessels that seek out these trans fats and remove them from the bloodstream. Thus, when we consume trans fats, they persist in our bloodstream for a very long time, compared to natural forms of fat. The longer these molecules spend in our bloodstream, the more they can contribute to the formation of clots, plaques, and hardened arteries. For this reason, the United States Food and Drug Administration has recently made a preliminary determination that trans fats are “not generally recognized as safe,” a determination that will likely lead to a complete ban on their presence in foodstuffs (Brownell & Pomeranz, 2014).

  • Phospholipids and glycolipids form cellular membranes

Perhaps the most important and basic function of lipids in living cells is in the formation of cellular membranes . All cells, from the most basic bacterium to those that form the most specialized human tissues, are surrounded by a plasma membrane made of lipid molecules . For more detail, see the Membranes I: Introduction to Biological Membranes module.

The lipids that form membranes are a special type called phospholipids (Figure 11). They are so named because they have a characteristic phosphate group (PO 4 ). Like triglycerides, the central structure of a phospholipid is the glycerol molecule . However, phospholipids have two fatty acid tails attached to the glycerol, whereas triglycerides have three. On the remaining carbon of the glycerol, a large, charged, phosphate-containing group is added.

Figure 11: A phospholipid.

Figure 11 : A phospholipid.

This distinctive head group gives phospholipids their unique properties. Like fatty acids , the presence of a hydrophobic tail and a hydrophilic head means that phospholipids are amphiphilic . This distinctive structure leads to a very peculiar behavior by phospholipids – the spontaneous formation of bilayers. When phospholipid molecules are placed into an aqueous solution (water-based), they will arrange themselves into sphere-shaped structures in which the surface of the sphere is a double layer of phospholipids. While the hydrophilic head groups are attracted to the water in the surrounding solution, the hydrophobic tails are repelled by it and attracted to each other. This means that the most “comfortable” arrangement for the phospholipids to take is to tuck their tails together in a water-free interior space, with the polar head groups facing out, interacting with water (Figure 12) – this is called a micelle Membranes I: Introduction to Biological Membranes module.

Figure 12: Three of the different structures phospholipids can form in an aqueous solution: micelle, liposome, and bilayer sheet. In this depiction, the hydrophilic heads are round and white and the hydrophobic tails are yellow wavy lines.

Figure 12 : Three of the different structures phospholipids can form in an aqueous solution: micelle, liposome, and bilayer sheet. In this depiction, the hydrophilic heads are round and white and the hydrophobic tails are yellow wavy lines.

  • Steroids provide structure and cell signaling

Another class of lipid molecules that are important in cells are the steroids, also called sterols. Unlike triglycerides and phospholipids with their long hydrocarbon tails, steroids consist of four fused carbon rings, as shown in Figure 13. As you would expect because of all of the nonpolar C-H bonds , steroids are not soluble in water.

Figure 13: The generic structure of a steroid molecule and the structure of cholesterol.

Figure 13 : The generic structure of a steroid molecule and the structure of cholesterol.

  • Cholesterol

The most fundamental steroid molecule is cholesterol because all of the other steroids that are made from it. Cholesterol has its own functions as well. For example, in animal cells , cholesterol is embedded in cell membranes to give them fluidity and to prevent them from solidifying in cold temperatures. Plants contain molecules similar to cholesterol called phytosterols that perform similar functions.

Cholesterol was named by Michel Chevreul in 1815, who found that human gallstones have a large amount of this lipid. A century later, Alfred Windaus and Henrich Wieland confirmed that the liver made cholesterol, although they deduced its structure incorrectly. They shared the Nobel Prize in 1928 for their discovery that cholesterol and other bile acids are made by the liver and used to dissolve dietary fats so that they can be absorbed by the intestines. The correct structure of cholesterol wasn't confirmed until 1945, when Dorothy Crowfoot Hodgkin used the new technique of X-ray diffraction (see Figure 14) to realize the precise arrangement of the four-ring structure (Bloch, 1982).

Figure 14: An x-ray diffraction pattern.

Figure 14 : An x-ray diffraction pattern.

  • Other steroids

There are many other steroids, but all of them, by definition, are cholesterol derivatives (Figure 15). That is, they are made using cholesterol as the starting material. Many of these steroids are hormones , such as the sex steroids estrogen, progesterone, testosterone, and their cousins. Other steroid hormones include cortisol and aldosterone.

Figure 15: A chart of the steroid hormones and their biosynthetic relationships.

Figure 15 : A chart of the steroid hormones and their biosynthetic relationships.

Although these hormones all perform widely differing functions in the body, they have a strikingly similar structure. This common structure means that they have a similar mechanism of action. Steroid hormones are released by glands and then travel throughout the body where they exert their actions by binding to their receptors inside of cells and then activating or de-activating genes . The power of steroid hormones is in their lipid nature, which allows them to cross biological membranes easily. Thus, a hormone produced in one tissue will quickly and easily diffuse throughout the entire body, passing through cells as easily as oxygen and carbon dioxide do (see Figure 16.)

Figure 16: A steroid hormone receptor's mechanism of action.

Figure 16 : A steroid hormone receptor's mechanism of action.

  • Other lipids

Several other sorts of compounds are grouped in with the lipid family because they are insoluble in water.

  • Carotenoids

The pigments that give some plants their orange and yellow color (e.g., carrots and summer squash) are carotenoids. They contain branching five-carbon chains called isoprene units (see Figure 17). Animals are able to break down these molecules into vitamin A, which may then be used to produce retinal, a pigment necessary for eyesight.

Figure 17: Isoprene units contain branching five-carbon chains. Animals are able to break down these molecules into vitamin A.

Figure 17 : Isoprene units contain branching five-carbon chains. Animals are able to break down these molecules into vitamin A.

Waxes appear in many different living things, providing the natural coating on some leaves and fruits, the sheen on the feathers of some birds, the shine on human hair, and the protective secretions in our ear canals. Like triglycerides, waxes are esters of fatty acids , consisting of an alcohol molecule bonded to fatty acids through ester linkage. Wax is strongly hydrophobic , and thus serves as an effective water repellant. In addition, the fully saturated hydrocarbon chains of wax molecules makes them solid at room temperature, like saturated fats discussed earlier (see Figure 18).

Figure 18: A wax molecule showing the long-chain alcohol and fatty acid.

Figure 18 : A wax molecule showing the long-chain alcohol and fatty acid.

  • Lipid research and medical science

Lipids play a role in eyesight, nerve tissue, vitamin absorption, the endocrine system , and many other body functions. Scientists have known that some fat is carried in the bloodstream ever since the late 1600s, when researchers examined the blood of animals that had just eaten a fatty meal and discovered that it briefly turned milky and yellowish. Now it’s clear that an excess of cholesterol in the blood can lead to deposits called plaque in artery walls, which increases a person’s risk of heart attack. Research into these fatty plaques has revealed that trans fats strongly exacerbate their formation, given how much longer they persist in the bloodstream. In addition, chemicals from cigarette smoke have been shown to increase the inflammatory response that gradually turns these fatty deposits into plaques and then to obstructive clots. Fortunately, arterial plaques are dynamic, and their formation can be reversed by stopping smoking and transitioning to a diet lower in cholesterol and fats from the saturated and trans fats family.

Ongoing research in lipid chemistry advances medical knowledge as we seek to understand and treat high cholesterol, heart disease, hormone disorders, thyroid disease, fatty liver disease, multiple sclerosis, autism spectrum disorder, macular degeneration, Guillain-Barré syndrome, and other conditions.

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Lipids Composition in Plant Membranes

Emilia reszczyńska.

Department of Plant Physiology and Biophysics, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, 20-033 Lublin, Poland

Agnieszka Hanaka

The paper focuses on the selected plant lipid issues. Classification, nomenclature, and abundance of fatty acids was discussed. Then, classification, composition, role, and organization of lipids were displayed. The involvement of lipids in xantophyll cycle and glycerolipids synthesis (as the most abundant of all lipid classes) were also discussed. Moreover, in order to better understand the biomembranes remodeling, the model (artificial) membranes, mimicking the naturally occurring membranes are employed and the survey on their composition and application in different kind of research was performed. High level of lipids remodeling in the plant membranes under different environmental conditions, e.g., nutrient deficiency, temperature stress, salinity or drought was proved. The key advantage of lipid research was the conclusion that lipids could serve as the markers of plant physiological condition and the detailed knowledge on lipids chemistry will allow to modify their composition for industrial needs.

Plants are constantly exposed to stress resulting from the conditions in which they are growing. They have to adapt to the external changes like humidity, salinity, or temperature. In order to maintain the normal physiological function and survive in the unfavorable environmental conditions, plants have developed defense mechanisms. Among them are alterations in the content of lipids, proteins or other molecules. For example, some of the plants are sensitive to temperature changes, e.g., Cucumis sativa L. [ 1 ] or Solanum lycopersicum L. [ 2 ], whereas others are less sensitive to temperature fluctuations, e.g., Arabidopsis thaliana L. [ 3 ] or Spinacia oleraceae L. These differences could be partially explained by the quantitative and qualitative changes in the lipid composition, which in turn triggers membrane fluidity and its function. Therefore, it is worth to present the selected lipid issues with the aim of explaining differences in their content, specific role in plants and emphasizing their impact in adverse conditions.

Classification of Fatty Acids in Plants

Nowadays, structure and role of about 400 different fatty acids are known in the plant kingdom [ 4 ]. Some of them are inevitable in the proper function of plant cells and some have positive effects on human health (e.g., anti-inflammatory [ 5 – 7 ], anticancer [ 8 , 9 ], antibacterial [ 10 ], and antiparasitic activity [ 11 ]) or are demanded in the different branches of industry, like food, pharmaceuticals, and cosmetics production [ 12 – 14 ].

The plant membranes are composed mainly of lipids which possess a hydrophilic, polar head attached to a glycerol backbone and a hydrophobic tail built of two fatty acids. Lipids form a hydrophobic barrier that separates cells and organelles from the environment [ 15 , 16 ]. The core building block of fatty acids is a hydrocarbon chain with a carboxyl group (-COOH) located on its terminal end. Based on the chain length of fatty acids, they are classified as: short-chain (aliphatic tails of up to 5 or even 7 carbons), medium-chain (aliphatic tails of 6–8 up to 12–14 carbons), long-chain (aliphatic tails of 13–18 up to 22 carbons), or very long-chain fatty acids (aliphatic tails longer than 22 carbons; >C22) [ 17 – 21 ]. Most often, the number of carbon atoms in the plant tissues is between 14 and 24. Moreover, the aliphatic chain can be saturated (saturated fatty acid, SFA) or unsaturated (unsaturated fatty acid, UFA), where all carbon–carbon linkages form single bonds, or some carbons are matched by one or more double bonds, respectively. In addition, UFA can be divided into monounsaturated (monoenoic) fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) with exactly one or at least two double bonds, respectively [ 22 , 23 ]. Fatty acids are the building blocks of lipids.

Nomenclature of Fatty Acids

According to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature of fatty acids, they can be formed using three systems of rules known as the shorthand formulas, the systematic names and the trivial names. The triple nomenclature can be demonstrated on one of the saturated fatty acids: C16:0—shorthand formula; hexadecenoic acid—systematic one; palmitic acid—trivial name. More complicated names can be constructed for the MUFA and PUFA, where one or more double bounds in acyl chain occur. In the case of the fatty acid possessing one double bound, C16:1 (n-7), it can be denoted as cis -hexadec-9-enoic acid (systematic formula) or palmitoleic acid (trivial name) [ 24 ]. For PUFA, two examples with different numbers of double bonds in the molecule are shown below in order to clarify the nomenclature. α -linolenic acid with the cis double bond located at the third region in carbon atom (n-3) marked from the end with methyl group is described as the omega (ω)-3 with the general structure CH 3 CH 2 (CH = CHCH 2 ) n COOH, where n shows the numbering of cis double bond from the methyl terminus [ 24 , 25 ]. In addition, the position of the double bond in the carbon chain can be designated by delta (Δ) before the full name of fatty acid, counting carbons from the carboxyl group [ 26 , 27 ]. Linoleic acid (C18:2) with 18 carbon chain and two cis double bonds at C-9 and C12 from the carboxyl acid group could be specified as: 18:2 cis -Δ 9 , cis -Δ 12 octadecadienoic acid; cis, cis -9,12-octadecadienoic acid or cis,cis -6,9-octadecadienoic acid. Sometimes PUFA are designated without ω (C18:3), but it is unequivocal and can be represented by a few different fatty acids: C18:3 ω 1, C18:3 ω 3, C18:3 ω 6, or C18:3 ω 9 [ 22 , 23 , 28 ]. The systematic names of fatty acids are derived from the names of the main straight chain by the substitution of suffix -e with -oic, e.g., hydrocarbon chain of C18 saturated fatty acid is octadecane and the acid is called octadecanoic acid (C18:0) [ 22 ]. The exemplary formula of fatty acid was presented in Fig. ​ Fig.1. 1 . Some trivial names of fatty acids origin from their natural sources, like palmitic acid, which was detected as a palm oil component; oleic acid (C18:1 cis -Δ 9 )—occurred in olive oil [ 24 ] and myristic acid (tetradecanoic acid)—was first identified in the Myristicaceae family [ 29 ].

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Exemplary formula of fatty acids. Fatty acids are numbered from -COOH group (Δ) and from -CH 3 group (ω). a Cis -oleic acid—18:1—is with one double bound Δ 9 (IUPAC: (9Z)-Octadec-9-enoic acid), b palmitoleic acid—16:1—is with one double bound Δ 9 (IUPAC: (9Z)-Hexadec-9-enoic acid), c linoleic acid—18:2—is with two double bounds Δ 9,12 (IUPAC: 9- cis ,12- cis octadecadienoic acid), d α-linolenic acid—18:3—is with tree double bounds Δ 9,12,15 (IUPAC: (9Z,12Z,15Z)-octadec-9,12,15-trienoic acid)

Fatty Acids Composition in Plants

Some of the plant families are more often implemented into the research on fatty acids. Among them are Fabaceae and Asteraceae. To the Fabaceae belong, i.e., Arachis hypogaea L. [ 30 ], Astragalus L. [ 31 ], Pisum sativum L. [ 32 ], and to Asteraceae: Anthemis altissima L. [ 33 ], A. arvensis L. [ 34 ], A. talyschensis L. [ 35 ], Chamaemelum nobile L. [ 36 ], Tagetes patula L. [ 37 ]. Other families also have their representatives in the experiments on lipids, e.g., Lauraceae with Cinnamomum camphora and Umbellularia californica [ 31 ], Vitaceae with Cissus populnea Guill. and Perr. [ 31 ], Polygonaceae with Fagopyrum esculentum and Brassicaceae with Arabidopsis thaliana . Species listed above are used in pharmacy and medicine, e.g., Astragalus (recommended in immune disorders) [ 31 ] and A. altissima (possess sedative, digestive and antimicrobial activity) [ 38 – 40 ]; nutrition, e.g., A. hypogaea, F. esculentum (applied in human diet); industry, e.g., C. camphora and U. californica (both used in biodiesel production, especially C12:0-14:0) [ 17 ]; and the research, e.g., A. thaliana [ 41 ].

The summary of various plant families, species and plant parts (such as the seeds, leaves, flowers, stem oils, and roots) in Table ​ Table1 1 shows the considerable quantitative and qualitative differences in the fatty acids composition. Below are presented some specific examples concerning the seeds, aerial parts, leaves, flowers, and leafy stems.

The exemplary composition of fatty acid in the selected plant families

a Average value for the genus Anthemis calculated on the basis of five different species, i.e., Anthemis cotula , A. macrotis , A. annua, A. austriaca, and A. santonicum [ 144 ]

The same parts of the different plants can vary significantly in the composition of fatty acids, e.g., in seeds. The seeds of peanuts ( A. hypogaea ) contained the highest amounts of oleic (C18:1) and linoleic (C18:2) acids reaching 50% and 30%, respectively [ 30 ]. In the essential oil from the aerial parts of A. arvensis , the palmitic acid achieved ~21% [ 42 ], whereas 8.8% in the seeds with the total PUFA/SFA ratio equal 7.17 [ 34 ]. In the seeds of C. populnea , the most abundant among fatty acids were palmitic (C16:0)—40%, oleic (C18:1n-9)—27%, stearic (C18:0)—16.5%, and linoleic (C18:2n-6)—11.86% acids. Oil from the C. papulnea seeds contained SFA, which makes it appropriate for frying food because it is stable at increasing temperatures and stay resistant to oxidation [ 43 ]. The highest relative content of fatty acids in the F. esculentum seeds was determined for linoleic (C18:2n-6) (in the range 35.54–47.57%), oleic (C18:1n-9) (in the range 20.96–40.76%), and palmitic (C16:0) (in the range 13.86–26.42%) acids and the range of their values was dependent on the plant part (whole grain, hulls and bran). In addition, other fatty acids were identified in smaller quantities, i.e., lauric (C12:0), myristic (C14:0), palmitoleic (C16:1), stearic (C18:0), α-linolenic (C18:3n-3), and arachidic (C20:0) acids [ 44 ]. Moreover, α-linoleic acid is a precursor of the phytohormone, jasmonic acid, which is involved in the response of plants to the biotic and abiotic stress conditions [ 30 ]. Furthermore, both in the transgenic and non-transgenic seeds of A. thaliana the most abundant fatty acids were 18:2 (~30%) and 18:3 (~19%) [ 30 ] and the PUFA/SFA ratio was 4.05 [ 34 ].

The leaves of plants like C. camphora and U. californica in the presence of thioesterases accumulated 52 and 40% of C12:0 and C14:0, respectively, which protected plants against the fatty acids modification and deprivation of the membrane homeostasis. Triacylglycerols compose the fatty acids, e.g., C12:0, C14:0, C16:0, but their proportion depends on the expression or co-expression of thioesterases in the plants. Fatty acids are very important during modification of the lipid profiles in the plant membranes because their unbalance causes undesirable chlorosis and cell death [ 17 ]. In A. talyschensis , the composition of fatty acids depended on the plant part, thus SFA in the flowers was 1.3% and in the leaves—9.4% and UFA was 17.7% in the flowers and 87.0% in the leaves—being not detected in the stem. The proportion of PUFA/SFA in the flowers and leaves was 13.62 and 9.25, respectively [ 35 ]. In addition, both leafy stems and flowers of C. nobile contained fatty acids: C16:0 (~18%), C18:1n-9 (~23%), C18:2n-6 (~29%), C18:3n-3 (~18%), and the proportion of PUFA/SFA was 1.72 [ 36 ].

Classification and Composition of Lipids in Plants

In the plant membranes, three main classes of lipids appear, i.e., glycerolipids, sphingolipids, and sterols (Fig. ​ (Fig.2). 2 ). The most abundant are glycerolipids, which are divided into four groups: phospholipids (PL), galactolipids (GL), triacylglycerols (TAG), and sulfolipids (SL) [ 45 , 46 ]. Phospholipids containing phosphorus are major constituents of the membranes and they have different head groups modified by choline, ethanolamine, serine, or inositol and are described as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI), respectively. Phospholipids are also characterized by different length and the degree of unsaturation of their fatty acyl chains. Variations in their properties have an impact on the membrane characteristics. This class of lipids is unevenly distributed between the different membranes in the cell [ 24 , 47 – 49 ]. By contrast, in photosynthetic membranes of plants the major constituents are the nonphosphorus galactolipids divided mainly into two classes, monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG). Moreover, the nonphosphorous are also sulfolipids with sulfur-containing lipid, sulfoquinovosyldiacylglycerol (SQDG) [ 50 ]. Both MGDG and DGDG and SQDG are synthesized exclusively in the chloroplasts [ 51 – 54 ]. Of the grana thylakoid membrane area, 20–30% is occupied by lipids, and the most part by proteins or photosynthetic protein complexes [ 55 , 56 ]. The thylakoid membranes in higher plants contain four glycerolipids: MGDG, DGDG, SQDG, and phosphatidylglycerol (PG) [ 57 ]. Of all chloroplast lipids, MGDG and DGDG can reach 52% and 26%, respectively [ 58 , 59 ]. The exemplary composition of glycerolipids in the membranes of spinach chloroplasts and their thylakoids are presented in Table ​ Table2 2 .

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Classification of plant membrane lipids [ 142 ]

Composition of lipids in the membranes of spinach chloroplasts and their thylakoids

The proportion of the lipids was calculated as the weight of the percentage of fatty acids [ 59 ]

Plant sphingolipids are grouped into four classes: glycosyl inositolphosphoceramides (GIPC), glucosylceramides (GCer), ceramides (Cer), and free long-chain bases (LCB) [ 60 , 61 ]. They are built of a ceramide backbone composed of a long-chain base and a long-chain fatty acid matched by esterification. Both Cer and LCB can be phosphorylated and de-phosphorylated and Cer, additionally, glucosylated [ 62 ]. The composition of LCBs is mainly formed from phytosphingosine and its desaturated form, but others are also known, e.g., sphinganine and sphingenine [ 63 ]. The quantity of sphingolipids differs significantly depending on the plant species and tissues, but mostly reaches up to 10% of the total lipids in plants [ 64 ]. In the total amount of sphingolipids in the leaves of Arabidopsis, the ratios of GIPC:GCer:Cer:LCB were as follows 64:34:2:0.5%, proving that GIPC and GCer were the most prevailing [ 65 ]. In the tonoplast, sphingolipids were detected in the range from 10 to 20% of the total membrane lipids [ 66 , 67 ].

In plants, over 250 different sterols (phytosterols) have been identified. Among them most frequently are detected these belonging to 4-desmethylsterols, i.e., campesterol, stigmasterol, and sitosterol [ 68 , 69 ]. Phytosterols can appear in the forms of free sterols, steryl esters, steryl glycosides, and acylated sterol glycosides [ 69 ].

Lipids Organization in Membranes

Fatty acids composition (with the proportion of saturated and unsaturated fatty acids) influences lipid composition (specific proportions) and organization in plant membranes. For example, the percentage content of lipids in the thylakoid membranes of green plants is as follows: MGDG~50%, DGDG~25–30%, SQDG~5–15%, PG~5–15% [ 70 , 71 ]. The most popular fatty acids in the skeleton of plant galactolipids are 18:3/16:3 as 34:6 MGDG, 18:3/18:3 as 36:6 MGDG, 18:3/16:0 as 34:3 DGDG, and 18:3/18:3 DGDG in the approximate proportion: 80%, 16%, 16%, 70%, respectively [ 72 ]. The biological membranes have different composition and contain the domains in their structure, called rafts, which are enriched in sphingolipids and sterols with reduced level of unsaturated fatty acids, esp. in phospholipids [ 73 ]. It means that rafts are structures of lesser fluidity than non-raft areas.

Lipids perform many functions (Table ​ (Table3). 3 ). Among others, they influence performance, regulation, and physical properties of the membranes [ 74 , 75 ], serve in the distribution, organization, and functioning of bilayer spanning proteins [ 76 ], are involved in compartmentalization of cells and organells and are integral components of the photosynthetic protein complexes of the electron transport chain [ 55 ]. Lipids can also form other structures, e.g., plastoglobules and stromules in the chloroplasts. Plastoglobules are lipid droplets enclosed in lipid monolayer, which is connected to the stroma leaflet of the thylakoid membrane. They can be found in high number in etioplasts and in plastids of senescent leaves. Stromules are tubular extensions of both chloroplast envelopes into the cytosol and filled with stroma, but deprived of thylakoids. The number of plastoglobules and stromules increases during environmental stresses [ 77 , 78 ].

Lipids role in plants and their importance for humans [ 27 , 40 , 145 , 146 ]

Lipids composition undergoes remodeling in the face of various physiological [ 30 , 73 , 79 – 82 ], and environmental conditions [ 83 – 85 ]. Moreover, the artificial membranes are composed and applied to broaden our understanding of nature. The model membranes mimicking the natural ones are dedicated to determining the network organization and reorganization of the molecules, structural and functional interactions and mechanisms in a simplified composition combined of a few different lipids (mostly two to five) (Table ​ (Table4). 4 ). Models of the artificially formed membranes are involved in the research on the molecular membrane architecture and structure [ 59 , 86 – 88 ] based on the fluorescence [ 88 ] and microscopic techniques [ 87 ], including photosynthetic performance [ 89 ], xanthophyll cycle analysis [ 87 , 90 , 91 ], and free radicals connection with the environmental stress in plants [ 92 ]. For example, the mixture of two lipids, MGDG:DGDG in 2:1 ratio can be applied as the model of plant lipids in thylakoids for the LHCII (light-harvesting complex) measurements [ 86 ].

Proportion of lipids in the model membranes

MGDG monogalactosyldiacylglycerol, DGDG digalactosyldiacylglycerol, PC phosphatidylcholine, SQDG sulfoquinovosyldiacylglycerol, POPG 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine, EPG Egg phosphatidylglycerol; PA phosphatidic acid, SL sulfoquinovosyldiglyceride, PI phosphatidylinositol, PE phosphatidylethanolamine, PG phosphatidylglycerol

Based on the type of the lipid phase produced by lipids in the aqueous systems, we differentiate the nonbilayer- and bilayer-forming lipids. Nonbilayer-forming lipids form the ordered solid phases and bilayer-forming ones—liquid-disordered phases [ 93 ] (Fig. ​ (Fig.3). 3 ). The nonbilayer-forming lipids possessing small polar head groups like MGDG and PE with elevated content of PUFAs form inverted micelles or tubular structures due to their cone-like shape and form an inverted hexagonal (H II ) phase when dispersed in the aqueous solutions. The important functions of MGDG are to promote membrane stacking, stabilizing the inner membrane leaflet in grana disc [ 88 ] and conservation of photosynthetic energy [ 94 ]. Furthermore, the proportion of the thylakoid nonbilayer lipids are crucial, because the higher content of the MGDG is responsible for the membrane permeability and thermal stability of PSII [ 71 ].

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Division of lipids based on the type of the lipid phase produced in aqueous systems

The bilayer-forming lipids with large head groups, such as DGDG, SQDG, PC, PG, and the decreased content of long-chain PUFAs exhibit a cylindrical shape and form the lamellar L α phase [ 72 , 93 – 96 ]. However, the increased ratio of DGDG to MGDG enhanced the stability of the thylakoid membrane [ 72 ]. Protein arrays are related with the phase transition of MGDG from a bilayer to a nonbilayer H II phase which was observed in the stress conditions, e.g., cold, low light [ 97 ], osmotic stress, and in fatty-acid mutants [ 98 ]. An association between lipids and protein organization is explained by the lateral membrane pressure hypothesis [ 99 ] known as ‘force from lipids’ (FFL) principle [ 100 ].

Lipids in Xanthophyll Cycle

The plants have developed the unique photoprotection mechanism, which prevents the excess absorption of light energy and consequently protects the photosynthetic apparatus from the oxidative damage. This process is called xanthophyll cycle [ 101 ]. In the xanthophyll cycle, the conversion of violaxanthin into zeaxanthin is done by violaxanthin deepoxidase (VDE) under high light [ 102 – 104 ]. VDE localizes to the thylakoid lumen and is regulated by lumen pH [ 90 , 105 ] and by binding to MGDG. It means that the MGDG molecules can serve as the docking sites for the xanthophyll cycle enzymes. In chloroplasts, H II can be established by MGDG, but in vitro VDE can also be stimulated by binding to PE [ 106 ]. The xanthophyll cycle pigments are located in the hydrophobic region of membrane with an easy access to the H II phase [ 93 , 107 ].

The studies concerning the location of the xanthophyll cycle in the transient membrane domain combined with LHCII, MGDG, VDE allowed to prove that MGDG have a crucial function in the stabilization of the structure of the LHCII protein in prevention its aggregation in PSII [ 71 ].

Synthesis of Glycerolipids in Plants

In plants, the most abundant class of lipids are glycerolipids, therefore first, their synthesis based on two pathways, then a brief view of the synthesis of PL, GL, TAG, and SL are presented.

Fatty acids are incorporated into glycerolipids in two different ways called the prokaryotic (plastidial) and the eukaryotic (cooperative) pathways located in the chloroplast and ER, respectively (Fig. ​ (Fig.4) 4 ) [ 15 , 16 , 108 , 109 ]. The prokaryotic pathway is involved in PG synthesis in all plants, but in the glycerolipid synthesis only in 16:3 plants (which means 16 acyl carbons and 3 double bonds) in the sn -2 position of MGDG molecule [ 110 ]. Moreover, 16:3 plants are those which produce up to half of the MGDG in the plastidial pathway [ 111 ]. The eukaryotic pathway is involved in the glycerolipid synthesis in all plants, but mostly in 18:3 plants (which means 18 acyl carbons and 3 double bonds) in the sn -2 position of MGDG molecule [ 110 ]. Irregardless pathway type, biosynthesis of membrane lipids starts from the formation of PAs, which are utilized to produce plastidic lipids or phospholipids. Phosphatidic acid produced in the chloroplasts can be converted to diacylglycerol (DAG), which then serves as a precursor for plastidic lipid synthesis [ 45 , 110 , 112 , 113 ]. PA is an intermediate molecule in the lipid synthesis and can be converted to and from PC and DAG because of the low energy requirements to remove them from membranes. PC could be a substrate for MGDG synthesis and DAG can be synthesized de novo with fatty acids, then removed from other lipids or derived from TAG turnover [ 111 ].

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Prokaryotic and eukaryotic pathways [ 45 , 110 , 113 ]

The prokaryotic pathway synthesizes four classes of glycerolipids: three glycolipid classes, i.e., MGDG, DGDG, trigalactosyldiacylglycerol (TGDG), and one sulfolipid class, SQDG. In the plant cell, 95% of fatty acids are produced by the plastidial fatty-acid synthase (FAS) belonging to the type I FAS [ 114 ]. First, coenzyme A (CoA) is converted into malonyl-CoA by acetyl-CoA carboxylase (ACCase) dependent on light [ 15 ]. Next, malonate is transferred to acyl carrier protein (ACP) by malonyl-CoA:ACP malonyltransferase (MCMT). Then, the activity of 3-ketoacyl-ACP synthase 3, 1, and 2 (KAS III, I, and II, respectively) give the main products of fatty-acid de novo synthesis: 16:0-ACP and 18:1Δ9- cis -ACP. Fatty-acid desaturation continues at high rate in the dark period [ 82 ].

By contrast, the eukaryotic pathway produces six phospholipid classes, i.e., phosphatidic acid (PA), PC, PE, PG, PI, and PS [ 115 ]. The eukaryotic pathway of 16:0/18:0 DAG moieties can produce around 20% of total DGDG. During the life cycle of plants, an active lipid exchange between the chloroplast and ER occurs via the import of the DAG moiety of PCs from the ER to the chloroplast envelope where it contributes to the DAG pool used to synthesize plastidic lipids [ 45 , 110 , 112 , 113 ].

Phosphatidylgycerol is synthesized in plastids, ER, and mitochondria and in chloroplasts it is predominantly synthesized via the prokaryotic pathway. Phosphatidylcholine, PE, and PI are synthesized in the ER membrane. Triacylglycerol is mainly synthesized in the ER and chloroplastic envelope membranes and accumulates within the membrane bilayer and subsequently forms lipid droplets in the cytosol [ 116 , 117 ].

Moreover, some plant species show various proportions between pro- and eukaryotic pathways [ 15 ]. For example, in Arabidopsis leaves in controlled conditions, ~50% of the chloroplastic glycolipids (MGDG, DGDG, and SQDG) are derived from the eukaryotic pathway, in which glycerolipids synthesized in the ER membrane are transferred to chloroplasts and converted into glycolipids [ 16 , 118 – 120 ]. Other plants produce only one lipid, PG, in the prokaryotic pathway [ 15 ] and as the result of evolution [ 121 ], this pathway diminished in 18:3 plants [ 15 ]. Due to the insufficient information on prokaryotic pathway in 16:3 plants [ 110 ], the research of this pathway will provide data allowing to better understand the physiological significance of the lipid evolution in plants.

The phospholipid biosynthesis can be divided into the assembly of the phosphatidic acid (PA), formation free or activated DAG, which may be the sources for the biosynthesis of the cellular glycerolipids [ 122 ], and formation of the head group to form the whole glycerolipid molecule [ 47 ]. Both, PE and PC are synthesized in plants in two main steps. The first one is the conversion of serine to ethanolamine catalyzed by serine decarboxylase and the next one is the attachment of phosphocholine or phosphoethanolamine to the DAG backbone, catalyzed by aminoalcohol aminophosphotransferase [ 47 ]. Free fatty acids are exported from chloroplasts [ 123 , 124 ].

The first step of galactolipid synthesis is the transfer of galactose from uridine diphosphate (UDP)-galactose (UDP-Gal) onto DAG in the presence of MGDG synthases. The second step is the transfer a galactose from UDP-Gal onto MGDG accompanied by digalactosyldiacylglycerol synthases. Both are localized to the outer envelope. Moreover, in order to introduce double bonds in MGDG and DGDG, different plastidial desaturases are synthesized in the inner [ 52 , 53 , 115 , 125 , 126 ] and outer envelope [ 114 ].

Synthesis of TAGs can be driven by different pathways. The most straightforward seems to be the pathway in which the acyltransferases were required for successive acylation of medium-chain fatty acid in the sn -2 and sn -3 position of TAGs. Then, diacylglycerol acyltransferase (DGAT) incorporated, e.g., PC molecules, onto the membrane [ 17 , 19 , 127 – 130 ]. TAGs can also be synthesized by PC involvement by application of its entire DAG molecule or acyl-CoA may be used as an acyl donor [ 15 ]. TAG is formed from the conversion of the DAG and in reaction of acylation, DAG can be converted to TAG [ 108 ].

Biosynthesis of SQDG comprises three enzymatic steps. Uridine triphosphate (UTP) and glucose-1-phosphate under action of the unique stroma-localized UDP-Glc pyrophosphorylase UGP3 produced UDP-glucose (UDP-Glc) [ 131 ]. Then, UDP-Glc and sulfite are converted into UDP-sulfoquinovose in the presence of stroma-localized UDP-sulfoquinovose synthase (SQD1) [ 132 ]. Next, sulfoquinovose is transferred to DAG and catalyzed by SQD2 localized in the inner envelope [ 99 ].

Understanding of lipids metabolism is essential to study their regulatory role in the plant growth and development.

Fatty Acids and Lipids Composition under Adverse Conditions

Fatty acids and lipids are examined in the research on the reconstitution of membrane system and the effects of stress conditions. The disturbed balance of the membrane caused reorganization of the lipid bilayer [ 126 ]. The influence of adverse environment, e.g., nutrient deficiency (especially nitrogen and phosphate), temperature stress (heat, cold, and freezing), salinity and drought on membrane lipid composition was expansively proved (Table ​ (Table5). 5 ). Fatty acids and lipids composition were dependent on the length of time incubation in adverse conditions [ 41 ] or the level of the unfavorable agents [ 133 ]. The observed trends can vary from an increase in the total amount of each lipid class [ 134 ] to the elevation [ 85 , 135 ] or decrease [ 136 ] of the specific fatty acids.

Lipid composition in plant membranes under adverse environmental conditions

MGDG monogalactosyldiacylglycerol, DGDG digalactosyldiacylglycerol, PC phosphatidylcholine, SQDG sulfoquinovosyldiacylglycerol, PA phosphatidic acid, SL sulfolipid, PI phosphatidylinositol, PE phosphatidylethanolamine, PG phosphatidylglycerol, PS phosphatidylserine, TAG triacylglycerol, DAG diacylglycerol

12:0—lauric acid, 14:0—myristic acid, 18:0—stearic acid, 18:1—oleic acid, 18:2—linoleic acid, 18:3—linolenic acid, 18:3-PG— linolenic acid containing phosphatidylglycerol, 16:0—palmitic acid, 16:1—palmitoleic acid, 16:1 -t — trans -Δ 3 -hexadecenoic acid, 16:3—hexadecenoic acid

FT protein-PC flowering locus T (FT) protein binding to phosphatidylcholine, FAD3 fatty-acid desaturase 3 (cytosolic), FAD8 fatty-acid desaturase 8 (plastidic)

There is a direct linkage between the variations in membrane fluidity and the changes in membrane thickness [ 137 ]. The content of UFA in lipid membranes increases with decreasing temperature, but constitutively higher levels of UFA do not lead to drought tolerance [ 138 ]. Moreover, higher quantity of PUFA in the seeds may result in their earlier maturity [ 138 ]. In the membranes, lipids are required for photosynthetic thermostability during elevation of temperature [ 139 , 140 ]. The right temperature is necessary to protect and stabilize the photosystems, allowing the plant to maintain a functional and efficient photosynthetic machinery [ 141 ]. Temperature elevation reduces the membrane thickness by hydrophobic interaction in the membrane [ 76 ]. Oppositely, upon lowering the environmental temperature lipid bilayers become more ordered and as a consequence they become thicker [ 137 ].

On the basis of Table ​ Table5, 5 , it seems that lipids may serve as the biomarkers susceptible for various environmental stresses. Therefore, our understanding of plant lipid biosynthesis and chemistry is essential for manipulation in lipids via biotechnology and implementing the results in different industrial sectors beneficial for humans, e.g., pharmacy, cosmetics, chemistry, nutrition (Table ​ (Table2), 2 ), e.g., Arabidopsis genes can be employed for decreasing the undesirable fatty acids in Nicotana tabacum [ 134 ].

Conclusions

The biosynthesis and lipid composition (the ratio of saturated to unsaturated acids) of biomembranes play a key role in the functioning of plants. During their growth, plants adapted to the adverse conditions through the reorganization of lipid membranes resulting from the change in the fatty-acid content and, consequently, the formation of lipids.

High level of lipids remodeling in plant membranes under different adverse conditions (e.g., nutrient deficiency, temperature stress, salinity, or drought) was proved. The elevation of UFA results in the membrane resistance to high temperatures, which allows plants to better adjust to the environmental changes. The crucial benefit resulting from the lipids research is that they could serve as the markers of plant physiological status. Moreover, better understanding of the biomembranes remodeling and lipids chemistry allows to generate changes desirable for different sectors of industry like pharmacy or agriculture and food science.

Compliance with Ethical Standards

The authors declare that they have no conflict of interest.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Uncovering how HIV assembles its lipid coat, which allows it to enter cells

Uncovering how HIV assembles its lipid coat, which allows it to enter cells

New insights into how the human immunodeficiency virus (HIV) curates and assembles its lipid envelope have been gleaned by RIKEN biologists. These findings into HIV biology could help to inform the search for new treatments. The paper is published in the journal Nature Communications .

A well-chosen outfit can open doors in the human world. The same holds true for HIV, which wraps itself in a coat of specialized lipids that greatly affects its ability to gain an entry into—and subsequently exit—host cells.

Like most viruses, HIV has only a bare-bones set of essential genes and lacks virtually all of the metabolic functions present in cells.

"Since viruses cannot synthesize lipids, HIV 'steals' lipids from the plasma membrane of host cells," explains Toshihide Kobayashi of the RIKEN Pioneering Project on Integrated Lipidology.

However, the biochemical composition of this membrane differs notably from that of the viral envelope, which is heavily enriched for two subtypes of lipids: cholesterol and sphingomyelin.

A viral protein called Gag facilitates the gathering of these lipids as newly replicated viruses "bud" from the membranes of infected cells, but the underlying mechanism was unclear.

To fathom the depths of this mystery, Kobayashi teamed up with researchers at the University of Strasbourg in France, where he also maintains a lab.

The expression of the HIV Gag protein is sufficient to drive plasma membrane budding in cultured human cells , and the team used a sophisticated multipronged imaging strategy to observe this process.

"Our lab has been developing and characterizing proteins that bind to specific lipids," says Kobayashi. The team labeled sphingomyelin- and cholesterol-binding proteins with fluorescent dyes. They then observed how these lipids behave during Gag-induced budding with cutting-edge microscopy methods that can resolve single molecules.

The plasma membrane consists of two layers: the inner and outer leaflets (named based on their position relative to the cellular interior).

The researchers observed that when Gag attached to the inner leaflet, it overlapped with islands of cholesterol and sphingomyelin on the outer leaflet, physically isolating these lipids. As more Gag proteins bound the leaflet and interacted with each other, sphingomyelin accumulation continued to increase.

As a consequence, the nearby surface of the membrane began to curve, further concentrating these lipid domains as a prelude to the final stages of the budding process.

These findings represent an important step forward to understanding HIV biology, but key questions remain. "We've shown that the inner leaflet protein reorganizes outer leaflet lipids, but we do not know how," says Kobayashi. "Our priority is to clarify this mechanism."

Journal information: Nature Communications

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  • Published: 26 February 2024

Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer

  • Sai Man Cheung 1   na1 ,
  • Kwok-Shing Chan 1 , 2 , 3   na1 ,
  • Wenshu Zhou 1 ,
  • Ehab Husain 4 ,
  • Tanja Gagliardi 1 , 5 ,
  • Yazan Masannat 1 , 6 , 7 &
  • Jiabao He 1 , 8  

Scientific Reports volume  14 , Article number:  4699 ( 2024 ) Cite this article

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  • Medical research

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman’s coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p  < .001), lower median (0.42 (0.02), p  < .001), a negative skewness with lower magnitude (− 1.65 (0.77), p  = .001), higher entropy (4.35 (0.64), p  = .007) and lower kurtosis (5.13 (3.99), p  = .001). Peri-tumoural PUFA had a lower mean ( p  < .001), lower median ( p  < .001), a positive skewness with higher magnitude ( p  = .005) and lower entropy ( p  = .002). Peri-tumoural SFA had a higher mean ( p  < .001), higher median ( p  < .001), a positive skewness with lower magnitude ( p  < .001) and lower entropy ( p  = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude ( p  = .01) and lower kurtosis ( p  = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness ( r s  = − .64), PUFA entropy ( r s  = .63) and SFA skewness ( r s  = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

Introduction

Oestrogen receptor-positive (ER +) breast cancer constitutes more than two-thirds of all postmenopausal cases 1 , which account for 75% of all new diagnoses. While hormonal treatment has had high efficacy in women with postmenopausal ER + breast cancer 2 , the typical hormonal regime requires maintenance therapy for 5 years, with adverse effects including blood clots, stroke and disruption to sexual and gynecologic quality of life 3 . Hence, an approach to determine the efficacy of hormonal therapy may allow for more precise and targeted treatment.

Oestrogen is predominantly modulated by mammary adipocytes in postmenopausal women 4 , and it induces the production of stearoyl-coenzyme-A desaturase-1 in ER + breast carcinoma cells 5 . An imbalance in overall lipid composition within the breast has been observed in postmenopausal women with ER + breast cancer based on loosely defined regions of interest 6 , 7 . Intratumoural spatial heterogeneity from q -space imaging reflects the spatial distribution of histological cellularity 8 , while higher entropy (increased heterogeneity in spatial distribution) 9 from dynamic contrast-enhanced (DCE) MRI is associated with worse survival outcomes in triple negative compared to ER +  10 or Luminal A 11 breast cancer. Adipocyte-derived free fatty acids support cancer cell development through activation of fatty acid oxidation to meet energy demand under glucose-starved condition 12 . Subsequently, breast cancer cells cultivated with adipocyte-derived free fatty acids undergo a metabolic switch towards anaerobic glycolysis for adenosine triphosphate production, and the metabolic shift is associated with increased epithelial to mesenchymal transition for improved colonisation of distant sites 13 . Pro-inflammatory polyunsaturated fatty acids (PUFA) stimulate inflammation of the tumour microenvironment 14 , and the recruitment of aromatase-enriched tumour-associated macrophages enable oestrogen synthesis and enhance ER + breast cancer proliferation 15 . Further, accelerated biosynthesis of monounsaturated fatty acids (MUFA) substantially increases storage of triglycerides as lipid droplets, an event linked to tamoxifen resistance 16 . Hence, peri-tumoural spatial heterogeneity of lipid composition may demonstrate sensitivity in determining response to hormonal therapy in postmenopausal ER + breast cancer.

The quantitative mapping of lipid composition in breast adipose and fibroglandular tissue is thus highly desirable. However, conventional method of single-voxel spectroscopy is limited to a single spatial location 17 , and the spatially resolved method of chemical shift imaging demands substantial scan time with susceptibility to the inhomogeneity in the scanner magnetic field 18 , 19 . Chemical shift-encoded imaging (CSEI) is a recently proposed method to allow lipid composition mapping in the thigh 19 , abdomen 20 and breast 21 within a clinically acceptable time frame and quantification of MUFA, PUFA and saturated fatty acids (SFA) in adipose tissues. A recent ex vivo study using CSEI showed deregulation of lipid composition in peri-tumoural adipose tissues in breast cancer 21 .

Tumours with pro-angiogenic and pro-metastatic profile show high infiltration density of CD163 antibody on tumour-associated macrophages to produce significantly higher levels of anti-inflammatory cytokine interleukin-10 22 . We therefore hypothesised that the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with ER + breast cancer deviates from the whole breast lipid composition in healthy controls and is associated with inflammatory activities from histopathological analysis. To probe this hypothesis, we conducted a two-group cross-sectional prospective study examining the peri-tumoural spatial heterogeneity of lipid composition on maps acquired from MRI scans in postmenopausal patients with breast cancer in comparison with age-matched controls.

This Health Insurance Portability and Accountability Act-compliant study, performed between September 2017 and June 2019, was approved by the North of Scotland Research Ethics Service (REC Reference: 16/NS/0077), and written informed consent was obtained from all participants.

Participants

Thirteen postmenopausal participants (mean age, 62 ± [SD] 6 years) with ER + invasive ductal carcinoma and 13 age-matched postmenopausal healthy controls (mean age, 65 ± 5 years) participated in the study. Controls were recruited subsequent to participants with breast cancer and were approximately age-matched with a discrepancy less than 5 years for each participant. Participants undergoing breast conservation surgery, with tumour size larger than 10 mm in diameter on mammography, with no previous malignancies, chemotherapy or radiotherapy prior to surgery were eligible. Participants with diabetes or on statins or cholesterol control drugs were excluded. Controls were not at population risk of breast cancer or at high risk (Fig.  1 ). The purpose of this study is to understand the role of peri-tumoural lipid composition in postmenopausal participant in preparation for future studies into hormonal therapy, hence breast density was not controlled during recruitment. However, breast density decreases with age 23 and the current study was conducted in postmenopausal women. Subsequently only one participant and two controls with dense breast were included.

figure 1

Flowchart of two-group cross sectional research study design. Thirteen postmenopausal patients with oestrogen receptor-positive, invasive ductal carcinoma and 13 age-matched healthy controls were eligible at initial screening and were consented into the study. All participants and controls underwent fasting blood tests on serum full lipid profile (total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol to HDL ratio) and C-reactive protein (CRP) prior to chemical shift-encoded imaging on a clinical 3T MRI scanner. Fat mapping image analysis was conducted to compute spatial heterogeneity of lipid constituents in the peri-tumoural region (Peri-P) and the whole breast of participants and controls (WB-P, WB-C). Mann Whitney U or Wilcoxon signed rank paired statistical tests were subsequently performed to compare values between the locations. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Clinical procedure

All participants underwent fasting blood tests 24 , and the samples were prepared 25 and batch-processed 26 at the Clinical Biochemistry Department of National Health Service Grampian for C-reactive protein (CRP) 27 and a full lipid profile (total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol to HDL ratio). Standard clinical histopathological examination was subsequently performed to determine histological tumour size, grade and Nottingham Prognostic Index 28 . Immunostaining was conducted in a single batch for tumour cellular proliferation marker Ki-67 29 and pro-inflammatory marker CD163 antibody on tumour-associated macrophages 22 with positive controls in breast tissue, appendix and tonsil and assessed quantitatively by a consultant pathologist (EH) with 20 years of experience in breast pathology. All 13 participants completed MRI scans. The post-surgery pathologic report showed one participant with mostly ductal carcinoma in situ (DCIS); we were unable to define the peri-tumoural region, and this participant was therefore excluded from analyses.

Lipid composition mapping

All images were acquired on a 3T whole-body clinical MRI scanner (Achieva TX, Philips Healthcare, Best, Netherlands), using a 16-channel breast coil for signal detection and a body coil for uniform transmission. Both T 1 - and T 2 - weighted anatomical images were acquired from all participants with additional diffusion-weighted images performed in patients to support tumour localisation, however administration of the contrast agent was not included in the study. T 1 -weighted images were acquired using a fast field echo sequence, with echo time of 2.9 ms, repetition time of 5.7 ms, matrix of 192 × 192, pixel size of 1.25 × 1.25 mm 2 , slice thickness of 2 mm. T 2 -weighted images were acquired using a turbo spin echo sequence, with echo time of 60 ms, repetition time of 5000 ms, matrix of 192 × 192, pixel size of 1.25 × 1.25 mm 2 , slice thickness of 2 mm. Diffusion-weighted images were acquired using a pulsed gradient spin echo sequence, with two b values of 0 and 800 s/mm 2 , echo time of 60 ms, repetition time of 4000 ms, matrix of 96 × 96, pixel size of 2.5 × 2.5 mm 2 , slice thickness of 4 mm. Lipid composition images were acquired from one breast (diseased breast in patients and left breast in healthy controls) using a two-dimensional CSEI sequence 18 , 19 with 174 echoes, an initial echo time of 1.14 ms, echo spacing of 1.14 ms, repetition time of 200 ms, flip angle of 15°, matrix of 64 × 64, pixel size of 3.75 × 3.75 mm 2 , slice thickness of 4 mm and 30 slices. The total acquisition time was 3.5 min.

Image analysis

Image analysis was conducted in MATLAB (R2020a, MathWorks Inc., Natick, MA, USA) and ImageJ (v1.52p, National Institute of Health, Bethesda, MD, USA) 30 . The maps showing the number of double bonds in triglycerides were computed from a subset of raw data (first 16 echoes) 18 prior to the calculation of quantitative maps of MUFA, PUFA and SFA as a percentage of the total amount of lipids 18 , 19 . Tumour boundary was delineated in all slices of tumour region of interest on the first echo of lipid composition images, with reference to anatomical and diffusion-weighted images, by a consultant radiologist with 15 years of experience in breast MRI examinations. Stringent measures were undertaken during the delineation of tumours and generation of the peri-tumoural regions. The dilation of the tumour region of interest, extraction of the peri-tumoural region and subsequent processing of the lipid composition maps were predefined with automated scripts. Consistent with previous clinical breast imaging studies analysing tumour microenvironment 31 , 32 , the peri-tumoural region was defined as an outward extension of 15 mm (4 voxels) from the tumour boundary forming a three-dimensional rim around the tumour (Peri-P; see Fig.  2 ). Our definition of the peri-tumoural region adopted the half way point from published literature, from a thickness of 9–12 mm 32 to a thickness of 20 mm 31 .

figure 2

Peri-tumoural and whole breast lipid composition maps, obtained from MRI scans, in a typical participant (65-year-old woman with oestrogen receptor-positive breast cancer) and a control participant (overlaid on anatomical image). ( a – c ) MUFA, PUFA and SFA maps in the whole breast of a control participant (WB-C). ( d – f ) MUFA, PUFA and SFA maps in the peri-tumoural region of a participant (Peri-P). ( g – i ) MUFA, PUFA and SFA maps in the whole breast of a participant (WB-P). For the control participant, the mid-sagittal slice is shown. For the participant, the slice at the greatest dimension of the tumour (central grey area) is shown. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

The whole breast was defined as containing only adipose and fibroglandular tissue in controls (WB-C), with further exclusion of the tumour in participants (WB-P). The chest cavity and the subcutaneous fat were removed from images in all participants and controls. Adipose voxels with lipid signals comprising over 60% of the total signal within regions of interest (the peri-tumoural region and the whole breast) were extracted from lipid composition maps for histogram analysis, in accordance with our prior ex vivo study to ensure adequate signal-to-noise ratio for the accuracy of lipid quantification 21 . The spatial heterogeneities (mean, median, skewness, entropy and kurtosis) 11 , 33 were subsequently computed based on histogram distribution for each lipid constituent, using the formulae published in our prior study 21 . Skewness indicates the deviation of a distribution from the normal distribution and has both polarity and magnitude. The polarity gives an indication of the relative position of mean and median, while the magnitude estimates the distance between the two. A system with random distribution of a single chemical constituent would assume a Gaussian symmetric bell shape with skewness at zero.

Sample size and power calculation

The effect size was based on an ex vivo study 21 considering the values of spatial heterogeneity of lipid composition in peri-tumoural breast adipose tissue. The mean of peri-tumoural MUFA in tumours with low and high grading scores was 0.40 ± 0.01 and 0.38 ± 0.02 respectively. Using standardised mean difference Cohen’s d , the estimated effect size was 1.2. The effect size was considered a conservative estimation and anticipated to be higher for comparison between participants and controls. With the average variance at 25% from our previous clinical data, we determined that a sample size of 12 participants per group has 80% power to detect a difference between participants and controls at a two-sided α  = 0.05 significance level.

Statistical analysis

All statistical analyses were performed in the R software (v3.6.3, The R Foundation for Statistical Computing, Vienna, Austria) using ‘stats’ and ‘Hmisc’ packages. Mann Whitney U tests were performed to compare the spatial heterogeneity of lipid constituents in the whole breast of participants versus controls (WB-P vs WB-C), and in the peri-tumoural region in participants versus the whole breast in controls (Peri-P vs WB-C). Wilcoxon signed rank paired tests were performed to assess the difference in lipid constituents in the peri-tumoural region compared with the whole breast in participants (Peri-P vs WB-P). The Spearman’s rank correlation coefficients ( r s ) and 95% confidence intervals (CI) were used to assess correlations between the spatial heterogeneity of each lipid constituent in the peri-tumoural region and tumour size, proliferative activity marker Ki-67 and pro-inflammatory marker CD163 antibody on tumour-associated macrophages. P  < 0.017 was considered to indicate a statistically significant difference for 3-group comparisons, after Bonferroni correction to avoid Type I errors in the multiplicity of statistical analysis.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the North of Scotland Research Ethics Service (Identifier: 16/NS/0077), and signed written informed consent was obtained from all participants prior to entry into the study.

Participant characteristics

The characteristics of the study participants are shown in Table 1 . For the cohort of postmenopausal participants, over 70% (18/25) had scattered fibroglandular tissue, and none had extreme proportion of fibroglandular tissue. There was no evidence of a difference in breast density, body mass index, and serum lipid profile between participants and controls. The histopathological findings in participants are shown in Table 2 . The peri-tumoural and the whole breast lipid composition maps from a participant and a typical control are shown in Fig.  2 .

Peri-tumoural region versus whole breast in participants

There were significant differences in mean, median, skewness, and entropy of all lipid constituents and kurtosis of MUFA (Fig.  3 , Table 3 ) between the peri-tumoural region and whole breast in participants. For MUFA, there was a lower mean ( p  < .001), lower median ( p  < .001), a negative skewness with lower magnitude ( p  = .001), higher entropy ( p  = .007), and lower kurtosis ( p  = .001) in the peri-tumoural region (Fig.  3 , Table 3 ). For PUFA, there was a lower mean ( p  < .001), lower median ( p  < .001), a positive skewness with higher magnitude ( p  = .005), and lower entropy ( p  = .002) in the peri-tumoural region, but no evidence of a difference in kurtosis (Fig.  3 , Table 3 ). For SFA, there was a higher mean ( p  < .001), higher median ( p  < .001), a positive skewness with lower magnitude ( p  < .001), and lower entropy ( p  = .012) in the peri-tumoural region, but no evidence of a difference in kurtosis (Fig.  3 , Table 3 ).

figure 3

The group difference in ( a ) mean, ( b ) median, ( c ) skewness, ( d ) entropy and ( e ) kurtosis of MUFA, PUFA, SFA in the whole breast of control participants (WB-C) (n = 13), the peri-tumoural region (Peri-P) (n = 12) and the whole breast of participants (WB-P) (n = 12). Each dot represents a peri-tumoural or whole breast mean fraction or spatial heterogeneity, and the dots are organised in three columns corresponding to locations. All spatial heterogeneities are shown in boxplots to indicate the minimum, 25th percentile, median, 75th percentile and maximum. Mann Whitney U (participants versus control participants) and Wilcoxon signed rank paired (within participants) tests were performed between the groups. Statistical significant p values are marked by *(< .017 after Bonferroni correction for multiple comparisons), **(< .01), ***(< .001). ‘ns’: not significant. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Peri-tumoural region in participants versus whole breast in controls

For MUFA, there was a negative skewness with lower magnitude ( p  = .01) and lower kurtosis ( p  = .009) in the peri-tumoural region compared with the whole breast in controls (Fig.  3 , Table 3 ). There was no evidence of differences in other spatial heterogeneities of MUFA, nor in any spatial heterogeneities of PUFA or SFA.

Whole breast in participants versus whole breast in controls

When comparing the whole breast of participants with that of controls, we found there was no evidence of differences in mean, median, skewness, entropy and kurtosis of any lipid constituents (Fig.  3 , Table 3 ).

Correlation between peri-tumoural region and Ki-67 and CD163

MUFA skewness and kurtosis were not correlated with Ki-67 (Table 4 ). MUFA skewness had a moderate negative correlation ( p  = .03, Fig.  4 a, Table 4 ) with CD163. PUFA entropy had a moderate positive correlation ( p  = .03, Fig.  4 b, Table 4 ) with CD163. SFA skewness had a moderate positive correlation ( p  = .04, Fig.  4 c, Table 4 ) with CD163.

figure 4

Scatter plots showing correlations of ( a ) MUFA skewness (n = 12), ( b ) PUFA entropy (n = 12) and ( c ) SFA skewness (n = 12) with CD163 antibody on tumour-associated macrophages. The Spearman’s rank correlation coefficients ( r s ) and 95% confidence intervals (CI) are shown for each plot. MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids.

Correlation between peri-tumoural region and tumour size

The correlation between peri-tumoural lipid composition and tumour size is shown in Table 4 ; all correlation was nonsignificant.

In this in vivo investigation of peri-tumoural spatial heterogeneity of lipid composition in women with breast cancer, lipid composition maps acquired from MRI scans showed significant differences in mean, median, skewness and entropy of all lipid constituents between the peri-tumoural region and the whole breast in participants. The results demonstrated that the quantity and spatial distribution of peri-tumoural lipid composition were altered in postmenopausal women with ER + breast cancer, providing potential clinical markers to further the evidence from cellular and ex vivo studies. The difference in peri-tumoural MUFA in comparison to the whole breast in controls indicated the potential critical role of MUFA during tumour initiation. The degree of lipid deregulation was associated with CD163 antibody on tumour-associated macrophages, indicating the deployment of lipid in the peri-tumoural region as a dynamic process of inflammation during tumour progression.

Since MUFA showed significant differences in all the measures of peri-tumoural spatial heterogeneity compared with the whole breast in participants, MUFA might be the primary end product in lipid deregulation in the tumour microenvironment. Specifically, the lower mean and median of peri-tumoural MUFA compared with the whole breast suggests a tumour induced local reduction in MUFA. Both the polarity and magnitude of skewness have respective physical meaning in the context of this work. In the scenario of two pools (healthy and diseased), the polarity would indicate the dominant pool, while the magnitude indicating the balance between the two. We hence point out the polarity and magnitude in the results to allow a more direct conceptualisation of the underlying biological processes. The negative skewness for MUFA in both participants and controls indicates the distribution peaking at a higher value and extending further into lower values, while the lower magnitude of skewness in the peri-tumoural region indicates a more balanced distribution centred at a lower mean than the whole breast. Therefore, the tumour may induce regional reduction of MUFA in the breast within the adipose tissue adjacent to the tumour. The lower kurtosis and higher entropy of MUFA in the peri-tumoural region compared with the whole breast in participants indicate a more highly concentrated non-random distribution with less outliers and a more heterogeneous distribution, respectively 11 , 33 . It has been shown that there was a greater activity of the stearoyl-coenzyme-A desaturase-1 in ER + breast cancer cells than in ER- cells to accelerate MUFA production in breast cancer adipose tissues and generate phosphatidylcholine for membrane formation 34 . Thus, both the incorporation of MUFA into the tumour core to support membrane synthesis 35 and infiltration of breast carcinoma cells into peri-tumoural adipocytes 36 may lead to widespread MUFA reduction and heterogeneous spread 37 . The negative association between MUFA skewness in the peri-tumoural region and the CD163 antibody on tumour-associated macrophages suggests that spatial distribution of MUFA might impact pro-inflammatory activities.

There were significant differences in all spatial heterogeneity measures of PUFA, except for kurtosis; therefore, PUFA might be the secondary end product in lipid deregulation in the peri-tumoural region. The lower mean and median of PUFA in the peri-tumoural region compared with the whole breast in participants suggests increased uptake of exogenous PUFA to sustain the higher demand from tumour proliferation 38 and pro-inflammatory eicosanoid synthesis 36 . The positive skewness across groups indicates the distribution peaking at a lower value and extending into higher values, while the higher magnitude of skewness in the peri-tumoural region indicates more unbalanced distribution with a lower mean than the whole breast. The lower entropy of PUFA in the peri-tumoural region compared with the whole breast in participants indicates a more homogeneous distribution. PUFA remodels lipid droplets adjacent to the endoplasmic reticulum nuclear membrane to perturb the extracellular matrix architecture in MCF-7 (Luminal A, ER +) breast cancer cell lines with comparable impact on MDA-MB-231 (TNBC, ER-) cells 39 . The association between PUFA entropy in the peri-tumoural region with the CD163 antibody on tumour-associated macrophages suggests that PUFA may be involved in pro-inflammatory activities 36 , and may therefore be a critical surrogate for inflammation.

The elevated mean and median of SFA in the peri-tumoural region compared with the whole breast in participants suggests an extrusion of SFA from the tumour, with subsequent reduction in lipotoxicity and increased membrane rigidity for enhanced survival advantage 40 , as well as resistance to cancer therapies 41 . The positive skewness for SFA across groups indicates the distribution peaking at a lower value and extending into higher values, while the lower magnitude of skewness in the peri-tumoural region indicates a more balanced distribution centred at a higher mean than the whole breast. The lower entropy of SFA in the peri-tumoural region compared with the whole breast in participants indicates a more homogeneous distribution, potentially due to the uniform export of SFA across the tumour boundary 21 , 41 . An increased release of SFA in the tumour microenvironment stimulates macrophages to manufacture pro-inflammatory mediators, including cyclooxygenase-2 and tumour necrosis factor alpha 42 , leading to enhanced aromatase expression in adipocytes and sustained oestrogen biosynthesis for tumour progression 43 , 44 . However, MCF-7 cells are less sensitive to SFA modulation during nuclear membrane remodeling compared with MDA-MB-231 cells 39 . The association between SFA skewness in the peri-tumoural region and the CD163 antibody on tumour-associated macrophages suggests that SFA export might not only alleviate cell apoptosis but further support pro-inflammatory activities 41 . Therefore, the spatial heterogeneity of peri-tumoural SFA may reflect underlying inflammation, with the potential to become biomarkers for early diagnosis and response to therapy since an elevated level of macrophages is associated with higher recurrence and poorer prognosis 45 .

This prospective study adopted strict inclusion criteria to minimise the impact of confounding factors and answer a focused research question. All participants had invasive ductal carcinoma, with Luminal A or Luminal B ER + breast cancer, stage 2A or 2B. Given that less than 3 groups were analysed, correlation analyses were not conducted on peri-tumoural lipid composition within tumour type or stage categories. Lipid composition maps were acquired from a single breast to ensure optimal shimming and high image quality, and the classification of the peri-tumoural region in participants was well-defined, yielding consistency in comparisons. A comparison between the peri-tumoural region and the whole breast in controls answered a secondary research question on the potential of aberration in lipid composition as a clinical research tool for early diagnosis, with the ultimate aim to detect anomaly in the whole breast of women with a high risk of breast cancer.

Our study had limitations. First, this was a prospective study with a small cohort, and future large cohort studies are required to demonstrate the effectiveness of lipid composition as biomarkers for early diagnosis. Second, the investigation was a prospective study with recruitment of consecutive participants, with one participant and two controls with dense breast. Future cohort to focus on women with high density of the breast will be valuable. Third, this was not an interventional study, and the contribution of small but significant changes in heterogeneity of lipid composition will require future interventional studies to ascertain the clinical value of the imaging markers for determining the efficacy of hormonal therapy in postmenopausal patients with ER + breast cancer 46 . Fourth, a comparison between the peri-tumoural region and the whole breast in controls might be impacted by extreme values, although represented a tangible step forward in comparison to loosely defined regions of interest 6 , 7 . A refined reference to account for specific breast tissue and anatomy other than the whole breast may be devised in a future study to enhance our understanding of the role of lipids in breast cancer.

There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Chemical shift-encoded imaging

Oestrogen receptor-positive

Monounsaturated fatty acids

Polyunsaturated fatty acids

Saturated fatty acids

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Acknowledgements

The authors would like to thank Dr Matthew Clemence (Philips Healthcare Clinical Science, UK) for clinical scientist support, Dr Vasiliki Mallikourti, Ms Shona Davidson, Ms Louisa Pirie, Ms Fiona Geddes, Ms Kate Shaw for support on patient recruitment, Ms Kim Blake, Ms Brenda Still, Ms Dawn Younie for logistic support, Ms Nichola Crouch, Ms Laura Reid and Mr Michael Hendry for radiographer support. The authors would also like to thank Dr Beatrix Elsberger for providing access to the patients.

This project was funded by Friends of Aberdeen and North Centre for Haematology, Oncology and Radiotherapy (ANCHOR) (RS2016 004). Sai Man Cheung’s PhD study was jointly supported by Elphinstone scholarship, Roland Sutton Academic Trust and John Mallard scholarship and is currently funded by Cancer Research UK (C68628/A28312). The funding sources were not involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report nor in the decision to submit the article for publication.

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These authors contributed equally: Sai Man Cheung and Kwok-Shing Chan.

Authors and Affiliations

School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

Sai Man Cheung, Kwok-Shing Chan, Wenshu Zhou, Tanja Gagliardi, Yazan Masannat & Jiabao He

Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA

Kwok-Shing Chan

Department of Radiology, Harvard Medical School, Boston, MA, USA

Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, UK

Ehab Husain

Department of Radiology, Royal Marsden Hospital, London, UK

Tanja Gagliardi

Broomfield Breast Unit, Broomfield Hospital, Mid and South Essex NHS Trust, Chelmsford, UK

Yazan Masannat

London Breast Institute, Princess Grace Hospital, London, UK

Faculty of Medical Sciences, Newcastle Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

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Contributions

S.M.C. managed the study paperwork, recruited the patients, collected the data, analysed the data, interpreted the results and drafted the manuscript. K.S.C. optimised the image acquisition, analysed the data, interpreted the results and drafted the manuscript. W.Z. analysed the preliminary data, interpreted the results and reviewed the manuscript. E.H. performed the histopathological analysis, interpreted the results and reviewed the manuscript. T.G. performed the radiological analysis, interpreted the results and reviewed the manuscript. Y.M. recruited the patients, performed the surgical intervention and reviewed the manuscript. J.H. secured the funding, designed the study, coordinated the experiments, interpreted the results and drafted the manuscript.

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Correspondence to Sai Man Cheung .

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Cheung, S.M., Chan, KS., Zhou, W. et al. Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer. Sci Rep 14 , 4699 (2024). https://doi.org/10.1038/s41598-024-55458-y

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    Lipid droplets emerge from the endoplasmic reticulum (ER). The correct shape and composition of the ER membranes, which are likely affected by the fat storage-inducing transmembrane 2 (FIT2 ...

  22. Lipids Composition in Plant Membranes

    Fatty acids composition (with the proportion of saturated and unsaturated fatty acids) influences lipid composition (specific proportions) and organization in plant membranes. For example, the percentage content of lipids in the thylakoid membranes of green plants is as follows: MGDG~50%, DGDG~25-30%, SQDG~5-15%, PG~5-15% [ 70, 71 ].

  23. Uncovering how HIV assembles its lipid coat, which allows it to enter cells

    New insights into how the human immunodeficiency virus (HIV) curates and assembles its lipid envelope have been gleaned by RIKEN biologists. These findings into HIV biology could help to inform ...

  24. The biophysics and cell biology of lipid droplets

    Cellular lipid droplets store lipids as reservoirs for metabolic energy and membrane precursors. Lipid droplets form the dispersed phase of a cellular emulsion in the aqueous cytosol. Principles ...

  25. Polymers

    FVPT1, a novel heteropolysaccharide, was purified from the fruiting body of Flammulina velutipes using magnetic-field-assisted three-phase partitioning and gel permeation chromatography. The structure was characterized using monosaccharide composition and methylation analysis, infrared spectroscopy and nuclear magnetic resonance (NMR). The FVPT1 (~1.64 × 104 Da) was composed of L-fucose, D ...

  26. Spatial heterogeneity of peri-tumoural lipid composition in

    Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid ...