lipid

/lip"id, luy"pid/, n. Biochem.

any of a group of organic compounds that are greasy to the touch, insoluble in water, and soluble in alcohol and ether: lipids comprise the fats and other esters with analogous properties and constitute, with proteins and carbohydrates, the chief structural components of living cells.

Also, lipide /lip"uyd, -id, luy"puyd, -pid/.

[1920-25; LIP- + -ID³]

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Any of a diverse class of organic compounds, found in all living things, that are greasy and insoluble in water.

One of the three large classes of substances in foods and living cells, lipids contain more than twice as much energy (calories) per unit of weight as the other two (proteins and carbohydrates). They include the fats and edible oils (e.g., butter, olive oil, corn oil), which are primarily triglycerides; phospholipids (e.g., lecithin), which are important in cell structure and metabolism; waxes of animal or plant origin; and sphingolipids, complex substances found in various tissues of the brain and nervous system. Since insolubility is the defining characteristic, cholesterol and related steroids, carotenoids (see carotene), prostaglandins, and various other compounds are also classifiable as lipids.

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▪ biochemistry

Introduction

 any of a diverse group of organic compounds including fats, oils, hormones, and certain components of membranes that are grouped together because they do not interact appreciably with water. One type of lipid, the triglycerides (lipid), is sequestered as fat in adipose cells (adipose cell), which serve as the energy-storage depot for organisms and also provide thermal insulation. Some lipids such as steroid hormones (lipid) serve as chemical messengers between cells, tissues, and organs, and others communicate signals between biochemical systems within a single cell. The membranes (membrane) of cells and organelles (structures within cells) are microscopically thin structures formed from two layers of phospholipid molecules. Membranes function to separate individual cells from their environments and to compartmentalize the cell interior into structures that carry out special functions. So important is this compartmentalizing function that membranes, and the lipids that make them up, must have been essential to the origin of life itself.

      Water is the biological milieu—the substance that makes life possible—and almost all the molecular components of living cells, whether they be found in animals, plants, or microorganisms, are soluble in water. Molecules such as proteins, nucleic acids, and carbohydrates have an affinity for water and are called hydrophilic (“water-loving”). Lipids, however, are not hydrophilic but hydrophobic (“water-fearing”). Some lipids are amphipathic; that is, part of their structure is hydrophilic and another part, usually a larger section, is hydrophobic. Amphipathic lipids exhibit a unique behaviour in water: they spontaneously form ordered molecular aggregates, with their hydrophilic ends on the outside, in contact with the water, and their hydrophobic parts on the inside, shielded from the water. This property makes them the basis for the cellular and organelle membranes.

      Although biological lipids are not large macromolecular polymers like proteins, nucleic acids, and polysaccharides, many are formed by the chemical linking of several small constituent molecules. Many of these molecular building blocks are similar, or homologous, in structure. The homologies allow lipids to be classified into a few major groups: fatty acids, fatty acid derivatives, cholesterol and its derivatives, and lipoproteins. This article covers the major groups and explains how these molecules function as energy-storage molecules, chemical messengers, and structural components of cells.

Fatty acids (fatty acid)

      Fatty acids (fatty acid) rarely occur as free molecules in nature but are usually found as components of many complex lipid molecules such as fats (energy-storage compounds) and phospholipids (the primary lipid components of cellular membranes). This section describes the structure and physical and chemical properties of fatty acids. It also explains how living organisms obtain fatty acids, both from their diets and through metabolic breakdown of stored fats.

Structure

 Biological fatty acids, members of the class of compounds known as carboxylic acids, are composed of a hydrocarbon chain with one terminal carboxyl group (COOH). The fragment of a carboxylic acid not including the hydroxyl (OH) group is called an acyl group. Under physiological conditions in water, this acidic group usually has lost a hydrogen ion (H⁺) to form a negatively charged carboxylate group (COO⁻). Most biological fatty acids contain an even number of carbon atoms because the biosynthetic pathway common to all organisms involves chemically linking two-carbon units together (although relatively small amounts of odd-number fatty acids do occur in some organisms). The chemical structure of the ionized form of stearic acid (C₁₈) is shown in the figure—> in both carbon skeleton and space-filling representations. (C₁₈ indicates a hydrocarbon chain with 18 carbon atoms.) Although the molecule as a whole is water-insoluble by virtue of its hydrophobic hydrocarbon chain, the negatively charged carboxylate is hydrophilic. This common form for biological lipids—one that contains well-separated hydrophobic and hydrophilic parts—is called amphipathic.

      In addition to straight-chain hydrocarbons, fatty acids may also contain pairs of carbons linked by one or more double bonds, methyl branches, or a three-carbon cyclopropane ring near the centre of the carbon chain.

Saturated fatty acids

  common saturated fatty acidsThe simplest fatty acids are unbranched, linear chains of CH₂ groups linked by carbon-carbon single bonds with one terminal carboxylic acid group, as shown in the diagram—> of stearic acid. The term saturated indicates that the maximum possible number of hydrogen atoms are bonded to each carbon in the molecule. Many saturated fatty acids have a trivial or common name as well as a chemically descriptive systematic name. The systematic names are based on numbering the carbon atoms, beginning with the acidic carbon. The table (common saturated fatty acids) gives the names and typical biological sources of the most common saturated fatty acids. Although the chains are usually between 12 and 24 carbons long, several shorter-chain fatty acids are biochemically important. For instance, butyric acid (C₄) and caproic acid (C₆) are lipids found in milk. Palm kernel oil, an important dietary source of fat in certain areas of the world, is rich in fatty acids that contain 8 and 10 carbons (C₈ and C₁₀).

Unsaturated fatty acids

  Common Monounsaturated Fatty AcidsUnsaturated fatty acids have one or more carbon-carbon double bonds. The term unsaturated indicates that fewer than the maximum possible number of hydrogen atoms are bonded to each carbon in the molecule. The number of double bonds is indicated by the generic name—monounsaturated for molecules with one double bond or polyunsaturated for molecules with two or more double bonds. Oleic acid, shown in the figure—>, is an example of a monounsaturated fatty acid. Common representative monounsaturated fatty acids together with their names and typical sources are listed in the table (Common Monounsaturated Fatty Acids). The prefix cis-9 in the systematic name of palmitoleic acid denotes that the position of the double bond is between carbons 9 and 10. Two possible conformations, cis and trans, can be taken by the two CH₂ groups immediately adjacent to the double-bonded carbons. In the cis configuration, the one occurring in all biological unsaturated fatty acids, the two adjacent carbons lie on the same side of the double-bonded carbons. In the trans configuration, the two adjacent carbons lie on opposite sides of the double-bonded carbons.

       Common Polyunsaturated Fatty AcidsFatty acids containing more than one carbon-carbon double bond (polyunsaturated fatty acids) are found in relatively minor amounts. The multiple double bonds are almost always separated by a CH₂ group (−CH₂−CH=CH−CH₂−CH=CH−CH₂−), a regular spacing motif that is the result of the biosynthetic mechanism by which the double bonds are introduced into the hydrocarbon chain. The table (Common Polyunsaturated Fatty Acids) lists the most common polyunsaturated fatty acids, linoleic and arachidonic, together with several that are less common. Arachidonic acid (C₂₀) is of particular interest as the precursor of a family of molecules, known as eicosanoids (from Greek eikosi, “twenty”), that includes prostaglandins (prostaglandin), thromboxanes, and leukotrienes. These compounds, produced by cells under certain conditions, have potent physiological properties, as explained in the section Intracellular and extracellular messengers (lipid). Animals cannot synthesize two important fatty acids, linoleate and linolenate, that are the precursors of the eicosanoids and so must obtain them in the diet from plant sources. For this reason, these precursors are termed essential fatty acids.

      Trans polyunsaturated fatty acids, although not produced biosynthetically by mammals, are produced by microorganisms in the gut of ruminant animals such as cows and goats, and they are also produced synthetically by partial hydrogenation of fats and oils in the manufacture of margarine. There is evidence that ingestion of these trans acids can have deleterious metabolic effects.

Substituent groups

      In addition to the very common fatty acids with straight saturated or unsaturated acyl chains, many fatty acids are chemically modified by substituents on the hydrocarbon chain. For example, the preening gland of ducks secretes a fatty acid 10 carbons long with methyl (CH₃) groups substituted for one of the hydrogens on carbons 2, 4, 6, and 8. Some bacteria produce fatty acids that have a methyl group on the carbon atom farthest from the acidic group or on the penultimate carbon. Other bacteria incorporate a cyclopropane ring near the centre of the acyl chain. The bacterium that causes tuberculosis (Mycobacterium tuberculosis) synthesizes a whole family of cyclopropane-containing fatty acids called α-mycolic acids. Similar fatty acids are found in related bacteria. A third common constituent is a hydroxyl group (OH). Monohydroxyl acids are found in both plants and animals in relatively small amounts, but they are more prevalent in bacteria.

Physical properties

      Pure fatty acids form crystals that consist of stacked layers of molecules, with each layer the thickness of two extended molecules. The molecules in a layer are arranged so that the hydrophobic (water-fearing) hydrocarbon chains form the interior of the layer and the hydrophilic (water-loving) carboxylic acid groups form the two faces. For a specific fatty acid the details of the molecular packing may vary, giving rise to different crystal forms termed polymorphs.

      The melting temperatures of saturated fatty acids of biological interest are above 27 °C (81 °F) and rise with increasing length of the hydrocarbon chain. Monounsaturated and polyunsaturated molecules melt at substantially lower temperatures than do their saturated analogs, with the lowest melting temperatures occurring when the carbon-carbon double bonds are located near the centre of the hydrocarbon chain, as they are in most biological molecules. As a result, these molecules form viscous liquids at room temperature.

      The hydrophobic character of the hydrocarbon chain of most biological fatty acids exceeds the hydrophilic nature of the carboxylic acid group, making the water solubility of these molecules very low. For example, at 25 °C (77 °F) the solubility in grams of fatty acid per gram of solution is 3 × 10⁻⁶. Water solubility decreases exponentially with the addition of each carbon atom to the hydrocarbon chain. This relationship reflects the energy required to transfer the molecule from a pure hydrocarbon solvent to water. With each CH₂ group, for instance, more energy is required to order water molecules around the hydrocarbon chain of the fatty acid, which results in the hydrophobic effect.

      In pure water the carboxylate group can dissociate a positively charged hydrogen ion to only a very small degree thus:

R−COOH {long right arrow} RCOO⁻ + H⁺.

 Here R represents the hydrocarbon chain. The carboxylate ion, bearing a negative charge, is more polar than the undissociated acid. RCOOH can be converted completely to the ion RCOO⁻ by adding an equal number of molecules of a base such as sodium hydroxide (NaOH). This effectively replaces the H⁺ with Na⁺ to give the salt of the fatty acid, which is a soap (soap and detergent). The very useful detergent property of soaps stems from the fact that the RCOO⁻ anions in water spontaneously form stable, spherical aggregates called micelles, the general structure of which is shown in cross section in the figure—>. The interior of these structures, formed by the hydrocarbon chains, is an excellent solvent in which grease and hydrophobic dirt of all sorts can be sequestered. The diameter of each micelle is roughly twice the length of the extended fatty acid. Dispersions of micelles in water can be made quite concentrated and exhibit great cleansing power. These dispersions are stable and generally look very much like pure water. Bubbles and foams on the surface of soap dispersions are the result of the spontaneous adsorption of RCOO⁻ ions at the interface between the aqueous dispersion and air, with the result that the air-water interfaces are energetically stabilized and can therefore be mechanically expanded.

Chemical properties

      The most chemically reactive portion of fatty acids is the acidic carboxyl group (COOH). It reacts with alcohols (R′OH) to form products known as esters (ester) (RCOOR′) and releases water in the process. This ester bond is the principal covalent bond linking fatty acid moieties to other groups in the more-complex lipids discussed in other sections of this article. A second chemical bond, occurring much less frequently in biological lipids involving fatty acids, is the ether bond (R′−O−R). Ether bonds are chemically more stable than ester bonds.

      The hydrocarbon part of a fatty acid molecule is quite resistant to chemical attack unless carbon-carbon double bonds are present. A number of different kinds of molecules react with such a double bond. For example, when a catalyst such as platinum is present, hydrogen gas adds to the double bond to give a saturated fatty acid. Halogens (chlorine, bromine, and iodine) and their derivatives such as hydroiodic acid (HI) also react with the double bond to form saturated fatty acids, but in these cases one or two atoms of the halogen replace one or two of the hydrogens normally found in the saturated acyl chain. Carbon-carbon double bonds can also react with oxygen in either nonenzymatic processes or enzymatically catalyzed oxidation reactions. This process generates a variety of products, some of which contribute to the rancid smell in spoiled meat and vegetable products. In general, the more highly unsaturated the fatty acid, the more easily it is oxidized.

Biological sources

      Fatty acids are found in biological systems either as free molecules or as components of more-complex lipids. They are derived from dietary sources or produced by metabolism, as described below.

digestion of dietary fatty acids

      The main source of fatty acids in the diet is triglycerides (triglyceride), generically called fats. In humans, fat constitutes an important part of the diet, and in the more-developed countries it can contribute as much as 45 percent of energy intake. Triglycerides consist of three fatty acid molecules, each linked by an ester bond to one of the three OH groups of a glycerol molecule. After ingested triglycerides pass through the stomach and into the small intestine, detergents called bile salts are secreted by the liver via the gall bladder and disperse the fat as micelles. Pancreatic enzymes called lipases (lipase) then hydrolyze the dispersed fats to give monoglycerides and free fatty acids. These products are absorbed into the cells lining the small intestine, where they are resynthesized into triglycerides. The triglycerides, together with other types of lipids, are then secreted by these cells in lipoproteins, large molecular complexes that are transported in the lymph and blood to recipient organs. In detail, the process of triglyceride or fat absorption from dietary sources is quite complex and differs somewhat depending upon the animal species.

Storage

      After transport through the circulation, triglycerides are hydrolyzed yet again to fatty acids in the adipose tissue. There they are transported into adipose cells, where once again they are resynthesized into triglycerides and stored as droplets. Fat or adipose tissue essentially consists of cells the interior of which is largely occupied by a fat droplet. The triglyceride in these droplets is available to the body on demand as communicated to adipose tissue by hormone messengers.

      Various animals store triglycerides in different ways. In sharks, for example, fat is stored in the liver, but in bony fish it is deposited in and around muscle fibres. Insects store fat in a special organ called the fat body. The development of true adipose tissue is found only in higher animals.

Biosynthesis

      In mammals, fatty acids are synthesized in adipose and liver cells from glucose via a fairly complex pathway. In essence, the six carbons of a glucose molecule are oxidized to a pair of two-carbon carboxylic acid fragments called acetate. The starting point for biosynthesis is an acetate group chemically linked to a molecule of CoA (coenzyme A). The process of building up the acyl chain of a fatty acid then begins, basically through the sequential chemical addition of two-carbon fragments from CoA-acetate to generate, for example, the 16-carbon saturated fatty acid palmitate. This process is catalyzed by a complex enzyme known as fatty acid synthase. Elongation of the palmitate carbon chain and the introduction of carbon-carbon double bonds are carried out subsequently by other enzyme systems.

      The overall process is basically the same in organisms ranging from bacteria to humans. The required energy is supplied by oxidation of part of the carbon in a glucose molecule to carbon dioxide (CO₂) as follows: 4¹/₂ molecules of glucose plus 4 molecules of oxygen yield 1 molecule of palmitic acid plus 11 molecules of CO₂ plus a small surplus of available energy as 5 molecules of ATP, the chemical energy currency of the cell.

Fatty acid derivatives

Triglycerides

Structure

 Triglycerides (chemical name triacylglycerol), the principal means of storing fatty acids in biological systems, are a class of compounds that consist of glycerol (a three-carbon trihydroxy alcohol) with a fatty acid linked to each of the three OH groups by an ester bond. The chemical structure of a typical triglyceride, tristearin, is shown in the figure—>. Because this molecule contains only one type of fatty acid, it is referred to as a simple triglyceride. Almost all naturally occurring triglyceride molecules, however, contain more than one type of fatty acid; when two or more in a given molecule are different, it is called a mixed triglyceride. For any specific combination of three fatty acids, three different molecules are possible, depending upon which of the three fatty acids is bonded to the central carbon of glycerol. Considering the numbers of common saturated, monounsaturated, and polyunsaturated fatty acids, it is evident that there are a great many different triglycerides.

Physical properties

      Triglycerides are hydrophobic substances that are soluble only in some organic solvents. Unlike many other types of complex lipids, they possess no electric charges and are therefore referred to as neutral lipids. The molecular structure of a few triglycerides that have been studied in crystals indicates that the acyl chains on the 1 and 2 carbons of glycerol, together with the 1 and 2 carbons of glycerol itself, form a straight line. Carbon 3 projects at right angles to this line, but the acyl chain on its glycerol folds over at the carboxyl carbon to lie alongside the acyl chain on carbon 1. Triglyceride molecules look much like a tuning fork and, when packed together, produce layered crystals.

      The melting temperatures of mixed triglycerides are roughly an average of the melting temperatures of their constituent fatty acids. In simple triglycerides, melting temperatures rise with increasing acyl chain length but drop with increasing number of double bonds. Melted triglycerides are generally quite viscous oils. From the physiological standpoint, it is important that most stored triglycerides be fluid at body temperature in order to permit their rapid mobilization as an energy source. Liquidity is also important since subcutaneous stored fats perform an insulating function that must not interfere with the mobility of the organism and its parts.

Waxes (wax)

      A second group of neutral lipids that are of physiological importance, though they are a minor component of biological systems, are waxes. Essentially, waxes consist of a long-chain fatty acid linked through an ester oxygen to a long-chain alcohol. These molecules are completely water-insoluble and generally solid at biological temperatures. Their strongly hydrophobic nature allows them to function as water repellents on the leaves of some plants, on feathers, and on the cuticles of certain insects. Waxes also serve as energy-storage substances in plankton (microscopic aquatic plants and animals) and in higher members of the aquatic food chain. Plankton apparently use the biosynthesis of waxes to adjust their buoyant density and thus their depth in the ocean. It has been suggested that a major source of petroleum found in deep-sea sediments originates from the deposition of wax-rich dead plankton over vast periods of time. Whales and many fishes also store large quantities of waxes.

Biological membrane lipids

      The three principal classes of lipids that form the bilayer matrix of biological membranes are glycerophospholipids, sphingolipids, and sterols (principally cholesterol). The most important characteristic of molecules in the first two groups is their amphipathic structure—well separated hydrophilic (polar) and hydrophobic (nonpolar) regions. Generally, their shape is elongated, with a hydrophilic end or head attached to a hydrophobic moiety by a short intervening region of intermediate polarity. Because of the segregation of polarity and nonpolarity, amphipathic molecules in any solvent will spontaneously form aggregates that minimize energetically unfavourable contacts (by keeping unlike regions of molecules apart) and maximize favourable contacts with the solvent (by keeping similar regions of molecules together). The molecular arrangement of the aggregate depends upon the solvent and the details of the amphipathic structure of the lipid.

 In water, micelles formed by soaps (the sodium or potassium salts of fatty acids) are one such aggregate. The polar or hydrophilic portion of the soap molecules forms the surface of the micelle, while the hydrocarbon chains form its interior and are thus completely protected from the energetically unfavourable contact with water, as described in the section Fatty acids: Physical properties (lipid). Biological membrane lipids, however, do not form spherical micelles in water but instead form topologically closed lamellar (layered) structures, as shown in the figure—>. The polar heads of the component molecules form the two faces of the lamella, while the hydrophobic moieties form its interior. Each lamella is thus two molecules in thickness, with the long axis of the component molecules perpendicular to the plane of the bilayer.

 Other types of aggregates are also formed in water by certain amphipathic lipids. For example, liposomes are artificial collections of lipids arranged in a bilayer, having an inside and an outside surface, as shown in the figure—>. The lipid bilayers form a sphere that can trap a molecule inside. The liposome structure can be useful for protecting sensitive molecules that are to be delivered orally.

Glycerophospholipids

 Lipids of this class are the most abundant in biological membranes; their general structure is shown in the figure—>. In glycerophospholipids, fatty acids (given the generic labels R1 and R2) are linked through an ester oxygen to carbons 1 and 2 of glycerol, the backbone of the molecule. Phosphate is ester-linked to carbon 3, while any one of several possible substituents (R3) is also linked to the phosphate moiety. Glycerophospholipids are amphipathic—glycerol and phosphate form the polar end of the molecule, while hydrocarbon chains form the nonpolar end. Although the fatty acids can be any of those common in biological systems, usually those attached to carbon 1 are saturated and those attached to carbon 2 are unsaturated. The various combinations of two fatty acids give rise to many different molecules bearing the same R3 group. Since this is true for each head group, there are altogether about a thousand possible types of glycerophospholipids. The great majority are found in biological membranes.

      From the standpoint of physical properties, the greatest difference among various molecules lies in the particular R3 substituent. This is due in part to the different sizes of the various types of R3 and in part to differences in their electric charges. The phosphatidylcholines and phosphatidylethanolamines are zwitterionic, meaning they have one negative and one positive charge on R3. Phosphatidic acid, phosphatidylserine, and phosphatidylinositol have a net negative charge. Differences in fatty acid composition also contribute to differences in physical properties of a series of molecules with the same R3. In the presence of an excess of water, the molecules form aggregates with a variety of geometries, the most common of which is the bilayer.

      In bilayers many glycerophospholipids as well as sphingomyelin (discussed below) can be in either one of two states, gel or liquid-crystalline. In the solidlike gel state, the lipid molecules in each half of the bilayer are arranged in a two-dimensional lattice, with their two acyl chains in the extended form. With the application of heat, the gel converts into the liquid-crystalline state at some temperature characteristic of the lipid mixture. In this state the molecules in each half of the bilayer remain in a fairly regular two-dimensional lattice but are free to rotate about their long axes and slide laterally through the layer. Their acyl chains now undergo considerable motion, leading to transiently kinked conformations. These motions give the bilayer a quasi-liquid behaviour that is characteristic of the bilayers in all biological membranes.

Sphingolipids (sphingolipid)

 A second major class of lipids usually associated with the membranes surrounding cells is sphingolipids. The general structure of this group is shown in the figure—>. Sphingolipids are based on an 18-carbon amine alcohol, sphingosine, and to a much lesser extent on a 20-carbon analog, phytosphingosine. All but one generic member of this class have a simple or complex sugar (R2) linked to the alcohol on carbon 1. The single deviant member is sphingomyelin, a molecule with a phosphorylcholine group (the same polar head group as in phosphatidylcholine) instead of the sugar moiety, making it an analog of phosphatidylcholine. All sphingolipids have, in addition to the sugar, a fatty acid (R1) attached to the amino group of sphingosine. Among the sphingolipids, only sphingomyelin, a phospholipid, is a major component of biological membranes.

      The principal factor determining the physical properties of sphingolipids is the substituent group attached to carbon 1 of sphingosine. Minor variations in properties depend upon the particular fatty acid component. The glycosphingolipids, all containing a sugar attached to carbon 1 of sphingosine, have physical properties that depend primarily on the complexity and composition of this substituent. Two generic types of glycosphingolipids are recognized: neutral glycosphingolipids, which contain only neutral sugars, and gangliosides, which contain one or more sialic acid residues linked to the sugar. Many hundreds of different glycosphingolipids have been isolated, and many more unidentified types probably exist. Glycosphingolipids are found exclusively on the external surface of the cell membrane, where their sugar moieties often act as antigens and as receptors for hormones and other signaling molecules.

cholesterol and its derivatives

      Cholesterol may be the most intensely studied small molecule of biological origin. Not only are its complex biosynthetic pathway and the physiologically important products derived from it of scientific interest, but also the strong correlation in humans between high blood cholesterol levels and the incidence of heart attack and stroke (diseases that are the leading causes of death in Europe and North America) is of paramount medical importance. The study of this molecule and its biological origin have resulted in more than a dozen Nobel Prizes.

      Cholesterol is a prominent member of a large class of lipids called isoprenoids (isoprenoid) that are widely distributed in nature. The class name derives from the fact that these molecules are formed by chemical condensation of a simple five-carbon molecule, isoprene. Isoprenoids encompass diverse biological molecules such as steroid hormones (steroid hormone), sterols (cholesterol, ergosterol, and sitosterol), bile acids, the lipid-soluble vitamins (A, D, E, and K), phytol (a lipid component of the photosynthetic pigment chlorophyll), the insect juvenile hormones, plant hormones (gibberellins), and polyisoprene (the major component of natural rubber). Many other biologically important isoprenoids play more-subtle roles in biology.

Structure and properties

 The sterols are major components of biological membranes in eukaryotes (organisms whose cells have a nucleus) but are rare in prokaryotes (cells without a nucleus, such as bacteria). Cholesterol is the principal sterol of animals, whereas the major sterol in fungi is ergosterol and that in plants is sitosterol. The characteristic feature of each of these three important molecules is four rigidly fused carbon rings forming the steroid nucleus and a hydroxyl (OH) group on ring A (shown in the figure—>). One molecule is distinguished from another by the positions of the carbon-carbon double bonds and by the structure of the hydrocarbon side chain on ring D.

      Cholesterol and its relatives are hydrophobic molecules with exceedingly low water solubility. The overall hydrophobicity is negligibly affected by the hydrophilic OH group. The structure of cholesterol is such that it does not form aggregates in water, although it does shoehorn between the molecules of biological membranes, with its OH group located at the water-membrane interface. The stiff fused ring structure of cholesterol adds rigidity to liquid-crystalline phospholipid bilayers and strengthens them against mechanical rupture. Cholesterol is thus an important component of the membrane surrounding a cell, where its concentration may rise as high as 50 percent by weight.

Biosynthesis

      Cholesterol biosynthesis can be divided into four stages. The first stage generates a six-carbon compound called mevalonic acid from three two-carbon acetate units (derived from the oxidation of fuel molecules—e.g., glucose) in the form of acetyl-CoA, the same initial building block used to form biological fatty acids described in the section Fatty acids: Biosynthesis (lipid). In the second stage mevalonate is converted to a five-carbon molecule of isopentenyl pyrophosphate in a series of four reactions. The conversion of this product to a 30-carbon compound, squalene, in the third stage requires the condensation of six molecules of isopentenyl pyrophosphate. In the fourth stage the linear squalene molecule is formed into rings in a complex reaction sequence to give the 27-carbon cholesterol.

Biosynthetic derivatives

      Two classes of important molecules, bile acids and steroid hormones, are derived from cholesterol in vertebrates. These derivatives are described below.

Bile acids

      The bile acids and their salts are detergents that emulsify fats in the gut during digestion. They are synthesized from cholesterol in the liver by a series of reactions that introduce a hydroxyl group into ring B and ring C and shorten the acyl side chain of ring D to seven carbons with the terminal carbon changed to a carboxyl group. The resulting molecule, cholic acid—as well as chenodeoxycholic acid (a close relative lacking the OH on ring C)—are usually found in the form of their salts, in which the amino acids taurine and glycine are chemically linked to the side-chain carboxyl group. These detergents are secreted from the liver into the gall bladder, where they are stored before being released through the bile duct into the small intestine. After performing an emulsifying action that is essential in fat digestion (described in the section Fatty acids (lipid)), they are reabsorbed in the lower small intestine, returned through the blood to the liver, and reused. This cyclic process, called the enterohepatic circulation, handles 20 to 30 grams of bile acids per day in human beings. The small fraction that escapes this circulation is lost in the feces. This is the major excretory route for cholesterol (though a smaller fraction is lost through the normal sloughing of dead skin cells).

Steroid hormones (steroid hormone)

      The steroid hormones consume a very small fraction of the total cholesterol available in the organism, but they are very important physiologically. (See below Biological functions of lipids (lipid).) There are five principal classes, all derived from cholesterol: progestins (active during pregnancy), the glucocorticoids (promoting the synthesis of glucose and suppressing inflammatory reactions), the mineralocorticoids (regulating ion balances), estrogens (estrogen) (promoting female sex characteristics), and androgens (promoting male sex characteristics). With the exception of progesterone, all of these closely related biologically active molecules have in common a shortened side chain in ring D and, in some cases, an oxidized OH group on ring A. The individual molecules are synthesized on demand by the placenta in pregnant women, by the adrenal cortex, and by the gonads.

Regulation of cholesterol metabolism

      High blood levels of cholesterol have been recognized as a primary risk factor for heart disease. For this reason, much research has been focused on the control of cholesterol's biosynthesis, on its transport in the blood, and on its storage in the body. The overall level of cholesterol in the body is the result of a balance between dietary intake and cellular biosynthesis on the one hand and, on the other hand, elimination of cholesterol from the body (principally as its metabolic products, bile acids).

      As the dietary intake of cholesterol increases in normal persons, there is a corresponding decrease in absorption from the intestines and an increase in the synthesis and excretion of bile acids—which normally accounts for about 70 percent of the cholesterol lost from the body. The molecular details of these control processes are poorly understood.

      Regulation of cholesterol biosynthesis in the liver and other cells of the body is better understood. The initial enzyme that forms mevalonate in the first stage of biosynthesis is controlled by two processes. One is inhibition of the synthesis of this enzyme by cholesterol itself or a derivative of it. The other is regulation of the catalytic activity of the enzyme by phosphorylation/dephosphorylation in response to intracellular signals. Several pharmacological agents also inhibit the enzyme, with the result that unhealthy levels of cholesterol can be lowered over a period of time.

Transport and storage

      The normal human body contains about 100 grams of cholesterol, although this amount can vary considerably among healthy people. Approximately 60 grams of this total are moving dynamically through the organism. Because cholesterol is insoluble in water, the basis of the bodily fluids, it is carried through the circulatory system by transport particles in the blood called lipoproteins. These microscopic complexes (described in the section Lipoproteins (lipid)) contain both lipids and proteins that can accommodate cholesterol and still remain soluble in blood.

      Cholesterol is absorbed into the cells of the intestinal lining, where it is incorporated into lipoprotein complexes called chylomicrons and then secreted into the lymphatic circulation. The lymph ultimately enters the bloodstream, and the lipoproteins are carried to the liver. Cholesterol, whether derived from the diet or newly synthesized by the liver, is transported in the blood in lipoproteins (VLDL and LDL) to the tissues and organs of the body. There the cholesterol is incorporated into biological membranes or stored as cholesteryl esters—molecules formed by the reaction of a fatty acid (most commonly oleate) with the hydroxyl group of cholesterol. Esters of cholesterol are even more hydrophobic than cholesterol itself, and in cells they coalesce into droplets analogous to the fat droplets in adipose cells.

      Cholesterol is lost from cells in peripheral tissues by transfer to another type of circulating lipoprotein (HDL) in the blood and is then returned to the liver, where it is metabolized to bile acids and salts.

Lipoproteins (lipoprotein)

 Lipoproteins are lipid-protein complexes that allow all lipids derived from food or synthesized in specific organs to be transported throughout the body by the circulatory system. The basic structure of these aggregates, shown in the figure—>, is that of an oil droplet made up of triglycerides and cholesteryl esters surrounded by a layer of proteins and amphipathic lipids—very similar to that of a micelle, a spherical structure described in the section Fatty acids (lipid) . If the concentration of one or another lipoprotein becomes too high, then a fraction of the complex becomes insoluble and is deposited on the walls of arteries and capillaries. This buildup of deposits is called atherosclerosis and ultimately results in blockage of critical arteries to cause a heart attack or stroke. Because of the gravity of this condition, much research is focused on lipoproteins and their functions. The emphasis in the following discussion is therefore placed on human lipoproteins.

Classification and formation

       Human plasma lipoproteinsThere are four major classes of circulating lipoproteins, each with its own characteristic protein and lipid composition. They are chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Within all these classes of complexes, the various molecular components are not chemically linked to each other but are simply associated in such a way as to minimize hydrophobic contacts with water. The most distinguishing feature of each class is the relative amounts of lipid and protein. Because the lipid and protein composition is reflected in the density of each lipoprotein (lipid molecules being less dense than proteins), density, an easily measured attribute, forms the operational basis of defining the lipoprotein classes. Measuring density also provides the basis of separating and purifying lipoproteins from plasma for study and diagnosis. The table (Human plasma lipoproteins) gives a summary of the characteristics of the lipoprotein classes and shows the correlation between composition and density.

  Human plasma apolipoproteinsThe principal lipid components are triglycerides, cholesterol, cholesteryl esters, and phospholipids. The hydrophobic core of the particle is formed by the triglycerides and cholesteryl esters. The fatty acyl chains of these components are unsaturated, and so the core structure is liquid at body temperature. The table (Human plasma apolipoproteins) gives more details about the nine different protein components, called apoproteins, of the lipoprotein classes. With the exception of LDL, which contains only one type of apoprotein, all classes have multiple apoprotein components. All the apoproteins, like phospholipids, are amphipathic and interact favourably with both lipids and water. The participation of the individual lipoproteins in lipid transport is illustrated in the figure—>. A more-detailed consideration of the character and functions of these lipoprotein particles follows.

Chylomicrons

      Chylomicrons are the largest lipoproteins, with diameters of 75–600 nanometres (nm; 1 nm = 10⁻⁹ metre). They have the lowest protein-to-lipid ratio and therefore the lowest density. Chylomicrons are synthesized by the absorptive cells of the intestinal lining and are secreted by these cells into the lymphatic system (lymph), which joins the blood circulation at the subclavian vein. The triglyceride, cholesteryl ester, and free cholesterol content of these particles is derived from the digestion of dietary fat. Their primary destinations in peripheral areas are heart muscle, skeletal muscle, adipose tissue, and lactating mammary tissue. The transfer of triglycerides and cholesteryl esters to the tissues depletes the lipid-protein aggregates of these substances and leaves remnant chylomicrons, which are eventually taken up by the liver. The lipid and protein remnants are used to form VLDL and LDL, described below.

Very low-density lipoproteins (VLDL)

       Human plasma lipoproteinsVLDL is a lipoprotein class synthesized by the liver that is analogous to the chylomicrons secreted by the intestine. Its purpose is also to deliver triglycerides, cholesteryl esters, and cholesterol to peripheral tissues. VLDL is largely depleted of its triglyceride content in these tissues and gives rise to an intermediate-density lipoprotein (IDL) remnant, which is returned to the liver in the bloodstream. As might be expected (see table (Human plasma lipoproteins)), the same proteins are present in both VLDL and IDL.

Low-density lipoproteins (LDL)

 Low-density lipoproteins are derived from VLDL and IDL in the plasma and contain a large amount of cholesterol and cholesteryl esters. Their principal role is to deliver these two forms of cholesterol to peripheral tissues. Almost two-thirds of the cholesterol and its esters found in plasma (blood free of red and white cells) is associated with LDL.

High-density lipoproteins (HDL)

      Lipoproteins of this class are the smallest, with a diameter of 10.8 nm and the highest protein-to-lipid ratio. The resulting high density gives this class its name. HDL plays a primary role in the removal of excess cholesterol from cells and returning it to the liver, where it is metabolized to bile acids and salts that are eventually eliminated through the intestine. LDL and HDL together are the major factors in maintaining the cholesterol balance of the body. Because of the high correlation between blood cholesterol levels and atherosclerosis, high ratios of HDL to cholesterol (principally as found in LDL) correlate well with a lower incidence of this disease in humans.

Functions, origins, and recycling of apolipoproteins

       Human plasma apolipoproteinsThe nine classes of apoproteins listed in the table (Human plasma apolipoproteins) are synthesized in the mucosal cells of the intestine and in the liver, with the liver accounting for about 80 percent of production.

      Chylomicrons are synthesized in the intestinal mucosa. The cells of this tissue, although able to make most apoproteins, are the principal source of apoB (the B-48 form) and apoA-I. The apoC-II component of chylomicrons is an activator for a plasma enzyme that hydrolyzes the triglyceride of these complexes. This enzyme, called lipoprotein lipase, resides on the cell surface and makes the fatty acids of triglycerides available to the cell for energy metabolism. To some degree, the enzyme is also activated by apoC-II, present in minor amounts in chylomicrons.

      VLDL, the lipoprotein carrier for triglycerides synthesized in the liver and destined for use in the heart and muscle, has a complement of five apoproteins. Among them are apoB-100, a protein performing a structural role in the complex, and apoC-I, -II, and -III. The first two of these activate the enzymes lecithin cholesterol acyltransferase (LCAT) and lipoprotein lipase. Curiously, apoC-III, a minor component of both chylomicrons and VLDL, inhibits lipoprotein lipase. Following discharge of the triglycerides, the remnants of VLDL return to the liver.

      LDL contains a single apoprotein and is the principal carrier of cholesterol to the peripheral tissue as both the free sterol and esters. The discharge of the lipid contents of this complex requires the recognition of the LDL B-100 apoprotein by a receptor located on the surface of recipient cells. When the protein is bound to the receptor, the receptor-LDL complex is engulfed by the cell in a process known as endocytosis. The endocytosed LDL discharges its contents within the cell, and B-100 is degraded to free amino acids that are used to synthesize new proteins or are metabolized as an energy source. The elucidation of the process of cellular uptake of LDL by Michael Brown (Brown, Michael S.) and Joseph Goldstein (Goldstein, Joseph L.) earned them the Nobel Prize for Physiology or Medicine in 1985.

      The primary function of HDL with its complement of apoproteins is to take up cholesterol from the cells of the body and deliver it to the liver for its ultimate excretion as bile acids and salts. The major apoproteins are A-I, an LCAT activator, and A-II. All of the HDL apoproteins have their biosynthetic origin in the liver. When HDL is secreted by this organ, it is a small, flattened discoid devoid of cholesterol but containing phospholipids and the apoproteins. In the peripheral tissues, HDL picks up cholesterol from the surface membranes of cells and, through the agency LCAT, converts it into esters using acyl chains from phosphatidylcholine.

Biological functions of lipids

      The majority of lipids in biological systems function either as a source of stored metabolic energy or as structural matrices and permeability barriers in biological membranes. Very small amounts of special lipids act as both intracellular messengers and extracellular messengers such as hormones and pheromones (pheromone). Amphipathic lipids, the molecules that allow membranes to form compartments, must have been among the progenitors of living beings. This theory is supported by studies of several simple, single-cell organisms, in which up to one-third of the genome is thought to code for membrane proteins and the enzymes of membrane lipid biosynthesis.

Cellular energy source

      Fatty acids that are stored in adipose tissue as triglycerides are a major energy source in higher animals, as is glucose, a simple six-carbon carbohydrate. In healthy, well-fed humans only about 2 percent of the energy is derived from the metabolism of protein. Large amounts of lipids are stored in adipose tissue. In the average American male about 25 percent of body weight is fat, whereas only 1 percent is accounted for by glycogen (a polymer of glucose). In addition, the energy available to the body from oxidative metabolism of 1 gram of triglyceride is more than twice that produced by the oxidation of an equal weight of carbohydrate such as glycogen.

Storage of triglyceride in adipose cells

      In higher animals and humans, adipose tissue consisting of adipocytes (fat cells) is widely distributed over the body—mainly under the skin, around deep blood vessels, and in the abdominal cavity and to a lesser degree in association with muscles. Bony fishes have adipose tissue mainly distributed among muscle fibres, but sharks and other cartilaginous fishes store lipids in the liver. The fat stored in adipose tissue arises from the dietary intake of fat or carbohydrate in excess of the energy requirements of the body. A dietary excess of 1 gram of triglyceride is stored as 1 gram of fat, but only about 0.3 gram of dietary excess carbohydrate can be stored as triglyceride. The reverse process, the conversion of excess fat to carbohydrate, is metabolically impossible. In humans, excessive dietary intake can make adipose tissue the largest mass in the body.

      Excess triglyceride is delivered to the adipose tissue by lipoproteins in the blood. There the triglycerides are hydrolyzed to free fatty acids and glycerol through the action of the enzyme lipoprotein lipase, which is bound to the external surface of adipose cells. Apoprotein C-II activates this enzyme, as do the quantities of insulin that circulate in the blood following ingestion of food. The liberated free fatty acids are then taken up by the adipose cells and resynthesized into triglycerides, which accumulate in a fat droplet in each cell.

Mobilization of fatty acids (fatty acid)

 In times of stress when the body requires energy, fatty acids are released from adipose cells and mobilized for use (as shown in the figure—>). The process begins when levels of glucagon and adrenaline in the blood increase and these hormones bind to specific receptors on the surface of adipose cells. This binding action starts a cascade of reactions in the cell that results in the activation of yet another lipase that hydrolyzes triglyceride in the fat droplet to produce free fatty acids. These fatty acids are released into the circulatory system and delivered to skeletal and heart muscle as well as to the liver. In the blood the fatty acids are bound to a protein called serum albumin; in muscle tissue they are taken up by the cells and oxidized to carbon dioxide (CO₂) and water to produce energy, as described below. It is not clear whether a special transport mechanism is required for enabling free fatty acids to enter cells from the circulation.

      The liver takes up a large fraction of the fatty acids. There they are in part resynthesized into triglycerides and are transported in VLDL lipoproteins to muscle and other tissues. A fraction is also converted to small ketone molecules that are exported via the circulation to peripheral tissues, where they are metabolized to yield energy.

Oxidation of fatty acids

      Inside the muscle cell, free fatty acids are converted to a thioester of a molecule called coenzyme A, or CoA. (A thioester is a compound in which the linking oxygen in an ester is replaced by a sulfur atom.) Oxidation of the fatty acid–CoA thioesters actually takes place in discrete vesicular bodies called mitochondria (mitochondrion). Most cells contain many mitochondria, each roughly the size of a bacterium (7 to 10 micrometres, or millionths of a metre, in diameter), although in specialized cells they may be larger and have special shapes. The mitochondrion is surrounded by a double membrane system enclosing a fluid interior space called the matrix. In the matrix are found the enzymes that convert the fatty acid–CoA thioesters into CO₂ and water (the chemical waste products of oxidation) and also adenosine triphosphate (ATP), the energy currency of living systems. The process consists of four sequential steps.

      The first step is the transport of the fatty acid across the innermost of the two concentric mitochondrial membranes. The outer membrane is very porous so that the CoA thioesters freely permeate through it. The impermeable inner membrane is a different matter; here the fatty acid chains are transported across in the following way. On the cytoplasmic side of the membrane, an enzyme catalyzes the transfer of the fatty acid from CoA to a molecule of carnitine, a hydroxy amino acid. The carnitine ester is transported across the membrane by a transferase protein located in the membrane, and on the matrix side a second enzyme catalyzes the transfer of the fatty acid from carnitine back to CoA. The carnitine that is re-formed by loss of the attached fatty acid is transferred back to the cytoplasmic side of the mitochondrial membrane to be reused. The transfer of a fatty acid from the cytoplasm to the mitochondrial matrix thus occurs without the transfer of CoA itself from one compartment to the other. No energy is generated or consumed in this transport process, although energy is required for the initial formation of the fatty acid–CoA thioester in the cytoplasm.

      The second step is the oxidation of the fatty acid to a set of two-carbon acetate fragments with thioester linkages to CoA. This series of reactions, known as β-oxidation, takes place in the matrix of the mitochondrion. Since most biological fatty acids have an even number of carbons, the number of acetyl-CoA fragments derived from a specific fatty acid is equal to one-half the number of carbons in the acyl chain. For example, palmitic acid (C₁₆) yields eight acetyl-CoA thioesters. In the case of rare unbranched fatty acids with an odd number of carbons, one three-carbon CoA ester is formed as well as the two-carbon acetyl-CoA thioesters. Thus, a C₁₇ acid yields seven acetyl and one three-carbon CoA thioester. The energy in the successive oxidation steps is conserved by chemical reduction (the opposite of oxidation) of molecules that can subsequently be used to form ATP (adenosine triphosphate). ATP is the common fuel used in all the machinery of the cell (e.g., muscle, nerves, membrane transport systems, and biosynthetic systems for the formation of complex molecules such as DNA and proteins).

      The two-carbon residues of acetyl-CoA are oxidized to CO₂ and water, with conservation of chemical energy in the form of and NADH (cell) and a small amount of ATP. This process is carried out in a series of nine enzymatically catalyzed reactions in the mitochondrial matrix space. The reactions form a closed cycle, often called the citric acid, tricarboxylic acid (tricarboxylic acid cycle), or Krebs cycle (after its discoverer, Nobelist Sir Hans Krebs (Krebs, Sir Hans Adolf)).

      The final stage is the conversion of the chemical energy in NADH and FADH₂ formed in the second and third steps into ATP by a process known as oxidative phosphorylation. All the participating enzymes are located inside the mitochondrial inner membrane—except one, which is trapped in the space between the inner and outer membranes. In order for the process to produce ATP, the inner membrane must be impermeable to hydrogen ions (H⁺). In the course of oxidative phosphorylation, molecules of NADH and FADH₂ are subjected to a series of linked oxidation-reduction reactions. NADH and FADH₂ are rich in electrons and give up these electrons to the first member of the reaction chain. The electrons then pass down the series of oxidation-reduction reactions and in the last reaction reduce molecular oxygen (O₂) to water (H₂O). This part of oxidative phosphorylation is called electron transport.

      The chemical energy available in these electron-transfer reactions is conserved by pumping H⁺ across the mitochondrial inner membrane from matrix to cytoplasm. Essentially an electrical battery is created, with the cytoplasm acting as the positive pole and the mitochondrial matrix as the negative pole. The net effect of electron transport is thus to convert the chemical energy of oxidation into the electrical energy of the transmembrane “battery.” The energy stored in this battery is in turn used to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate by the action of a complex enzyme called ATP synthase, also located on the inner mitochondrial membrane. Peter Mitchell (Mitchell, Peter Dennis) received the Nobel Prize for Chemistry in 1978 for his discovery of the conversion of electron transport energy into a transmembrane battery and the use of this battery to generate ATP. It is interesting that a similar process forms the basis of photosynthesis—the mechanism by which green plants convert light energy from the Sun into carbohydrates and fats, the basic foods of both plants and animals. Many of the molecular details of the oxidative phosphorylation system are now known, but there is still much to learn about it and the equally complex process of photosynthesis.

      The β-oxidation also occurs to a minor extent within small subcellular organelles called peroxisomes in animals and glyoxysomes in plants. In these cases fatty acids are oxidized to CO₂ and water, but the energy is released as heat. The biochemical details and physiological functions of these organelles are not well understood.

Regulation of fatty acid oxidation

      The rate of utilization of acetyl-CoA, the product of β-oxidation, and the availability of free fatty acids are the determining factors that control fatty acid oxidation. The concentrations of free fatty acids in the blood are hormone-regulated, with glucagon stimulating and insulin inhibiting fatty acid release from adipose tissue. The utilization in muscle of acetyl-CoA depends upon the activity of the citric acid cycle and oxidative phosphorylation—whose rates in turn reflect the demand for ATP.

      In the liver the metabolism of free fatty acids reflects the metabolic state of the animal. In well-fed animals the liver converts excess carbohydrates to fatty acids, whereas in fasting animals fatty acid oxidation is the predominant activity, along with the formation of ketones. Although the details are not completely understood, it is clear that in the liver the metabolism of fatty acids is tightly linked to fatty acid synthesis so that a wasteful closed cycle of fatty acid synthesis from and metabolism back to acetyl-CoA is prevented.

Lipids in biological membranes (membrane)

 Biological membranes separate the cell from its environment and compartmentalize the cell interior. The various membranes playing these vital roles are composed of roughly equal weight percent protein and lipid, with carbohydrates constituting less than 10 percent in a few membranes. Although many hundreds of molecular species are present in any one membrane, the general organization of the generic components is known. All the lipids are amphipathic, with their hydrophilic (polar) and hydrophobic (nonpolar) portions located at separate parts of each molecule. As a result, the lipid components of membranes are arranged in what may be called a continuous bimolecular leaflet, or bilayer. The polar portions of the constituent molecules lie in the two bilayer faces, while the nonpolar portions constitute the interior of the bilayer. A cross section of a lipid bilayer is shown in the figure—>. This structure forms an impermeable barrier for essential, water-soluble substances in the cell and provides the basis for the compartmentalizing function of biological membranes.

      Some protein components are inserted into the bilayer, and most span this structure. These so-called integral, or intrinsic, membrane proteins have amino acids with nonpolar side chains at the interface between the protein and the nonpolar central region of the lipid bilayer. A second class of proteins is associated with the polar surfaces of the bilayer and with the intrinsic membrane proteins. The protein components are specific for each type of membrane and determine their predominant physiological functions. The lipid component, apart from its critical barrier function, is for the most part physiologically silent, although derivatives of certain membrane lipids can serve as intracellular messengers.

      The most remarkable feature of the general biomembrane structure is that the lipid and the protein components are not covalently bonded to one another or to molecules of the other group. This sheetlike structure, formed only by molecular associations, is less than 10 nm in thickness but many orders of magnitude larger in its other two dimensions. Membranes are surprisingly strong mechanically, yet they exhibit fluidlike properties. Although the surfaces of membranes contain polar units, they act as an electric insulator and can withstand several hundred thousand volts without breakdown. Experimental and theoretical studies have established that the structure and these unusual properties are conferred on biological membranes by the lipid bilayer.

Composition of the lipid bilayer

       Plasma membrane lipid composition Organelle membrane lipid compositionMost biological membranes contain a variety of lipids, including the various glycerophospholipids such as phosphatidyl-choline, -ethanolamine, -serine, -inositol (inositol), and -glycerol as well as sphingomyelin and, in some membranes, glycosphingolipids. (These compounds are described in the section Fatty acid derivatives (lipid).) Cholesterol, ergosterol, and sitosterol (described in the section Cholesterol and its derivatives (lipid)) are sterols found in many membranes. The relative amounts of these lipids differ even in the same type of cell in different organisms, as shown in the table (Plasma membrane lipid composition) on the lipid composition of red blood cell membranes from different mammalian species. Even in a single cell, the lipid compositions of the membrane surrounding the cell (the plasma membrane) and the membranes of the various organelles within the cell (such as the microsomes, mitochondria, and nucleus) are different, as shown in the table (Organelle membrane lipid composition) on various membranes in a rat liver cell.

      On the other hand, the lipid compositions of all the cells of a specific type in a specific organism at a given time in its life are identical and thus characteristic. During the life of an organism, there may be changes in the lipid composition of some membranes; the physiological significance of these age-related changes is unknown, however.

Physical characteristics of membranes

 One of the most surprising characteristics of biological membranes is the fact that both the lipid and the protein molecules, like molecules in any viscous liquid, are constantly in motion. Indeed, the membrane can be considered a two-dimensional liquid in which the protein components ride like boats. However, the lipid molecules in the bilayer must always be oriented with their polar ends at the surface and their nonpolar parts in the central region of the bilayer. The bilayer structure thus has the molecular orientation of a crystal and the fluidity of a liquid. In this liquid-crystalline state, thermal energy causes both lipid and protein molecules to diffuse laterally and also to rotate about an axis perpendicular to the membrane plane. In addition, the lipids occasionally flip from one face of the membrane bilayer to the other and attach and detach from the surface of the bilayer at very slow but measurable rates. Although these latter motions are forbidden to intrinsic proteins, both lipids and proteins can exhibit limited bobbing motions. Within this seemingly random, dynamic mixture of components, however, there is considerable order in the plane of the membrane. This order takes the form of a “fluid mosaic” of molecular association complexes of both lipids and proteins in the membrane plane. The plane of the biological membrane is thus compartmentalized by domain structures much as the three-dimensional space of the cell is compartmentalized by the membranes themselves. The domain mosaics run in size from tens of nanometres (billionths of a metre) to micrometres (millionths of a metre) and are stable over time intervals of nanoseconds to minutes. In addition to this in-plane domain structure, the two lipid monolayers making up the membrane bilayer frequently have different compositions. This asymmetry, combined with the fact that intrinsic membrane proteins do not rotate about an axis in the membrane plane, makes the two halves of the bilayer into separate domains.

      An interesting class of proteins is attached to biological membranes by a lipid that is chemically linked to the protein. Many of these proteins are involved in intra- and intercellular signaling. In some cases defects in their structure render the cells cancerous, presumably because growth-limiting signals are blocked by the structural error.

Intracellular and extracellular messengers

      In multicellular organisms (eukaryotes), the internal mechanisms that control and coordinate basic biochemical reactions are connected to other cells by means of nerves and chemical “messengers.” The overall process of receiving these messages and converting the information they contain into metabolic and physiological effects is known as signal transduction. Many of the chemical messengers are lipids and are thus of special interest here. There are several types of external messengers. The first of these are hormones such as insulin and glucagon and the lipids known collectively as steroid hormones. A second class of lipid molecules is eicosanoids, which are produced in tissues and elicit cellular responses close to their site of origin. They are produced in very low levels and are turned over very rapidly (in seconds). Hormones have sites of action that are remote from their cells of origin and remain in the circulation for long periods (minutes to hours).

Steroid hormones (steroid hormone)

      Lipid hormones invoke changes in gene expression; that is, their action is to turn on or off the instructions issued by deoxyribonucleic acid (DNA) to produce proteins that regulate the biosynthesis of other important proteins. Steroids are carried in the circulation bound singly to specific carrier proteins that target them to the cells in particular organs. After permeating the external membranes of these cells, the steroid interacts with a specific carrier protein in the cytoplasm. This soluble complex migrates into the cell nucleus, where it interacts with the DNA to activate or repress transcription, the first step in protein biosynthesis.

       Organs affected by steroid hormonesAll five major classes of steroid hormones produced from cholesterol (described above in the section Cholesterol and its derivatives (lipid)) contain the characteristic five rings of carbon atoms of the parent molecule. Progestins are a group of steroids that regulate events during pregnancy and are the precursors of the other steroid hormones. The glucocorticoids, cortisol, and corticosterones promote the biosynthesis of glucose and act to suppress inflammation. The mineralocorticoids regulate ion balances between the interior and the exterior of the cell. Androgens regulate male sexual characteristics, and estrogens perform an analogous function in females. The target organs for these hormones are listed in the table (Organs affected by steroid hormones).

Eicosanoids

      Three types of locally acting signaling molecules are derived biosynthetically from C₂₀ polyunsaturated fatty acids, principally arachidonic acid. Twenty-carbon fatty acids are all known collectively as eicosanoic acids. The three chemically similar classes are prostaglandins, thromboxanes, and leukotrienes. The eicosanoids interact with specific cell surface receptors to produce a variety of different effects on different tissues, but generally they cause inflammatory responses and changes in blood pressure, and they also affect the clotting of blood. Little is known about how these effects are produced within the cells of target tissues. However, it is known that aspirin and other anti-inflammatory drugs inhibit either an enzyme in the biosynthesis pathway or the eicosanoid receptor on the cell surface.

Intracellular second messengers (second messenger)

      With the exception of the steroid hormones, most hormones such as insulin and glucagon interact with a receptor on the cell surface. The activated receptor then generates so-called second messengers within the cell that transmit the information to the biochemical systems whose activities must be altered to produce a particular physiological effect. The magnitude of the end effect is generally proportional to the concentration of the second messengers.

       Tissue Affected by Phosphoinositide SecondAn important intracellular second-messenger signaling system, the phosphatidylinositol system, employs two second-messenger lipids, both of which are derived from phosphatidylinositol (see above Glycerophospholipids (lipid)). One is diacylglycerol (diglyceride), the other is triphosphoinositol. In this system a membrane receptor acts upon an enzyme, phospholipase C, located on the inner surface of the cell membrane. Activation of this enzyme by one of the agents listed in the table (Tissue Affected by Phosphoinositide Second) causes the hydrolysis of a minor membrane phospholipid, phosphatidylinositol bisphosphate. Without leaving the membrane bilayer, the diacylglycerol next activates a membrane-bound enzyme, protein kinase C, that in turn catalyzes the addition of phosphate groups to a soluble protein. This soluble protein is the first member of a reaction sequence leading to the appropriate physiological response in the cell. The other hydrolysis product of phospholipase C, triphosphoinositol, causes the release of calcium from intracellular stores. Calcium is required, in addition to triacylglycerol, for the activation of protein kinase C.

Thomas E. Thompson

Additional Reading

A well-written basic textbook that covers all aspects of lipid metabolism and function is Dennis E. Vance and Jean E. Vance (eds.), Biochemistry of Lipids and Membranes (1985). An advanced general biochemistry text with accessible material on lipids is Christopher K. Mathews, K.E. van Holde, and Kevin G. Ahern, Biochemistry, 3rd ed. (2000).Lipid structures, properties, and metabolism are collected in Frank D. Gunstone, John L. Harwood, and Fred B. Padley (eds.), The Lipid Handbook (1994). The premier book on biological membranes is Robert B. Gennis, Biomembranes: Molecular Structure and Function (1989). A readable compendium of information about lipids is contained in Donald M. Small, The Physical Chemistry of Lipids, vol. 4 of Handbook of Lipid Research (1986). A readable discussion of the structure and metabolism of lipoproteins is contained in Charles R. Scriver, Arthur L. Beaudet, William S. Sly, and David Valle, The Metabolic and Molecular Bases of Inherited Disease (1995).The discovery, biochemistry, and physical chemistry of sphingolipids are detailed in Julian N. Kanfer and Sen-itiroh Hakomori, Sphingolipid Biochemistry, vol. 3 of Handbook of Lipid Research (1983). A collection of scientific articles on lipids can be found in Robert M. Bell, John H. Exton, and Stephen M. Prescott (eds.), Lipid Second Messengers, vol. 8 of Handbook of Lipid Research (1996).Thomas E. Thompson

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