Harper's Biochemistry Chapter 21 - Lipids of Physiologic Significance PDF

S E C T I O N Metabolism of Lipids V C H A P T E R Lipids of Physiologic Significance Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, P...

S E C T I O N Metabolism of Lipids V C H A P T E R Lipids of Physiologic Significance Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 21 O B J E C TI V E S Define simple and complex lipids and identify the lipid classes in each group. Indicate the structure of saturated and unsaturated fatty acids, explain how After studying this chapter, the chain length and degree of unsaturation influence their melting point, give you should be able to: examples, and explain the nomenclature. Explain the difference between cis and trans carbon–carbon double bonds. Describe how eicosanoids are formed by modification of the structure of unsaturated fatty acids; identify the various eicosanoid classes and indicate their functions. Outline the general structure of triacylglycerols and indicate their function. Outline the general structure of phospholipids and glycosphingolipids and indicate the functions of the different classes. Appreciate the importance of cholesterol as the precursor of many biologically important steroids, including steroid hormones, bile acids, and vitamin D. Recognize the cyclic nucleus common to all steroids. Explain why free radicals are damaging to tissues and identify the three stages in the chain reaction of lipid peroxidation that produces them continuously. Describe how antioxidants protect lipids from peroxidation by either inhibiting chain initiation or breaking the chain. Recognize that many lipid molecules are amphipathic, having both hydrophobic and hydrophilic groups in their structure, and explain how this influences their behavior in an aqueous environment and enables certain classes, including phospholipids, sphingolipids, and cholesterol, to form the basic structure of biologic membranes. 205 206 SECTION V Metabolism of Lipids BIOMEDICAL IMPORTANCE COOH The lipids are a heterogeneous group of compounds, including A saturated fatty acid (palmitic acid, C16) fats, oils, steroids, waxes, and related compounds. They have the common property of being (1) relatively insoluble in water and COOH (2) soluble in nonpolar solvents such as ether and chloroform. They are important dietary constituents, not only because of A monounsaturated fatty acid (oleic acid, C18:1) the high energy value of fats (see Chapter 22), but also because essential fatty acids, fat-soluble vitamins, and other lipophilic COOH micronutrients are contained in the fat of natural foods. Dietary A polyunsaturated fatty acid (linoleic acid, C18:2) supplementation with long-chain ω3 fatty acids is believed to have beneficial effects in a number of chronic diseases, includ- FIGURE 21–1 Fatty acids. Examples of a saturated (palmitic ing cardiovascular disease, rheumatoid arthritis, and dementia. acid), monounsaturated (oleic acid), and a polyunsaturated (linoleic Fat is stored in adipose tissue, where it also serves as a ther- acid) fatty acid are shown. mal insulator in the subcutaneous tissues and around certain organs. Nonpolar lipids act as electrical insulators, allowing Because they are uncharged, acylglycerols (glycerides), choles- rapid propagation of depolarization waves along myelinated terol, and cholesteryl esters are termed neutral lipids. nerves. Lipids are transported in the blood combined with pro- teins in lipoprotein particles (see Chapters 25 and 26). Lipids FATTY ACIDS ARE ALIPHATIC have essential roles in nutrition and health, and knowledge of lipid biochemistry is necessary for the understanding of many CARBOXYLIC ACIDS important biomedical conditions, including obesity, diabetes Fatty acids occur in the body mainly as esters in natural fats mellitus, and atherosclerosis. and oils, but are found in the unesterified form as free fatty acids, a transport form in the plasma. Fatty acids that occur in natural fats usually contain an even number of carbon LIPIDS MAY BE SIMPLE, COMPLEX, atoms. The chain may be saturated (containing no double bonds) or unsaturated (containing one or more double OR DERIVED bonds) (Figure 21–1). 1. Simple lipids include fats, oils, and waxes which are esters of fatty acids with various alcohols: Fatty Acids Are Named After a. Fats: Esters of fatty acids with glycerol Corresponding Hydrocarbons b. Oils: Fats in the liquid state at room temperature The most frequently used systematic nomenclature names c. Waxes: Esters of fatty acids with higher molecular weight the fatty acid after the hydrocarbon with the same number monohydric alcohols and arrangement of carbon atoms, with -oic being substi- 2. Complex lipids are esters of fatty acids, which always con- tuted for the final -e (Genevan system). Saturated acids end tain an alcohol and one or more fatty acids, but which also in -anoic, for example, octanoic acid (C8) (from the hydrocar- have other groups. They can be divided into three types: bon octane), and unsaturated acids with double bonds end in a. Phospholipids: Contain a phosphoric acid residue. -enoic, for example, octadecenoic acid (oleic acid, C18) (from They frequently have nitrogen-containing bases (eg, the hydrocarbon octadecane). choline) and other substituents. In many phospholipids Carbon atoms are numbered from the carboxyl carbon the alcohol is glycerol (glycerophospholipids), but in (carbon no. 1). The carbon atoms adjacent to the carboxyl car- sphingophospholipids it is sphingosine, which contains bon (nos. 2, 3, and 4) are also known as the α, β, and γ carbons, an amino group. respectively, and the terminal methyl carbon is known as the b. Glycolipids (glycosphingolipids): Contain a fatty acid, ω- or n-carbon. sphingosine, and carbohydrate. Various conventions are used for indicating the number c. Other complex lipids: These include lipids such as and position of the double bonds (Figure 21–2); for example, sulfolipids and amino lipids. Lipoproteins may also be Δ9 indicates a double bond on the ninth carbon counting placed in this category. 3. Derived lipids are formed from the hydrolysis of both sim- ple and complex lipids. They include fatty acids, glycerol, steroids/sterols (including cholesterol), other alcohols, fatty aldehydes, ketone bodies (see Chapter 22), hydrocarbons, FIGURE 21–2 Nomenclature for number and position of double bonds in unsaturated fatty acids. Illustrated using oleic lipid-soluble vitamins and micronutrients, and hormones. acid as an example. In this example, C1 is the Δ 1 carbon and C18 is Some of these (eg, free fatty acids, glycerol) also act as pre- the ω or n-1 carbon. Thus oleic acid may be termed 18:1 ω9 (or n-9) cursor lipids in the formation of simple and complex lipids. or 18:1 Δ9.  CHAPTER 21 Lipids of Physiologic Significance 207 from carbon 1 (the α-carbon); ω9 or n-9 indicates a double TABLE 21–1 Saturated Fatty Acids bond on the ninth carbon counting from the ω- or n-carbon. Common Number of In animals, additional double bonds can be introduced only Name C Atoms Occurrence between an existing double bond at the ω9, ω6, or ω3 position and the carboxyl carbon (carbon 1), leading to three series of Acetic 2 Major end product of carbohydrate fermentation by rumen organisms fatty acids known as the ω9, ω6, and ω3 families, respectively. Butyric 4 In certain fats in small amounts Saturated Fatty Acids Contain No (especially butter). An end product of carbohydrate fermentation by rumen Double Bonds organismsa Saturated fatty acids may be envisaged as based on acetic acid Valeric 5 (CH3—COOH) as the first member of the series in which Caproic 6 CH2— is progressively added between the terminal CH3— and —COOH groups. Examples are shown in Table 21–1. Other Lauric 12 Spermaceti, cinnamon, palm kernel, higher members of the series are known to occur, particularly coconut oils, laurels, butter in waxes. A few branched-chain fatty acids have also been iso- Myristic 14 Nutmeg, palm kernel, coconut oils, lated from both plant and animal sources. myrtles, butter Palmitic 16 Common in all animal and plant fats Unsaturated Fatty Acids Contain One or More Double Bonds Stearic 18 Second most common saturated fatty acid in nature after palmitic acid. Unsaturated fatty acids (see Figure 21–1, Table 21–2, for More abundant in animal than in examples) may be further subdivided as follows: plant fats. 1. Monounsaturated (monoethenoid, monoenoic) acids, a Also formed in the cecum of herbivores and to a lesser extent in the colon of humans. containing one double bond. TABLE 21–2 Unsaturated Fatty Acids of Physiologic & Nutritional Significance Number of C Atoms and Number and Common Position of Common Double Bonds Family Name Systematic Name Occurrence Monoenoic acids (one double bond) 16:1;9 ω7 Palmitoleic cis-9-Hexadecenoic In nearly all fats 18:1;9 ω9 Oleic cis-9-Octadecenoic Possibly the most common fatty acid in natural fats; particularly high in olive oil 18:1;9 ω9 Elaidic trans-9-Octadecenoic Hydrogenated and ruminant fats Dienoic acids (two double bonds) 18:2;9,12 ω6 Linoleic all-cis-9,12- Corn, peanut, cottonseed, soy bean, and Octadecadienoic many plant oils Trienoic acids (three double bonds) 18:3;6,9,12 ω6 γ-Linolenic all-cis-6,9,12- Some plants, eg, oil of evening primrose, Octadecatrienoic borage oil; minor fatty acid in animals 18:3;9,12,15 ω3 α-Linolenic all-cis-9,12,15- Frequently found with linoleic acid but Octadecatrienoic particularly in linseed oil Tetraenoic acids (four double bonds) 20:4;5,8,11,14 ω6 Arachidonic all-cis-5,8,11,14- Found in animal fats; important Eicosatetraenoic component of phospholipids in animals Pentaenoic acids (five double bonds) 20:5;5,8,11,14,17 ω3 Timnodonic all-cis-5,8,11,14,17- Important component of fish oils, eg, cod Eicosapentaenoic liver, mackerel, menhaden, salmon oils Hexaenoic acids (six double bonds) 22:6;4,7,10,13,16,19 ω3 Cervonic all-cis-4,7,10,13,16,19- Fish oils, algal oils, phospholipids in brain Docosahexaenoic 208 SECTION V Metabolism of Lipids O COOH LTA4 FIGURE 21–3 Prostaglandin E2 (PGE2). OH OH COOH 2. Polyunsaturated (polyethenoid, polyenoic) acids, contain- ing two or more double bonds. LXA4 3. Eicosanoids: These compounds, derived from eicosa OH (20-carbon) polyenoic fatty acids (see Chapter 23), com- prise the prostanoids, leukotrienes (LTs), and lipoxins FIGURE 21–5 Leukotriene and lipoxin structure. Examples (LXs). Prostanoids include prostaglandins (PGs), prosta- shown are leukotriene A4 (LTA4) and lipoxin A4 (LXA4). cyclins (PGIs), and thromboxanes (TXs). same side of the bond, it is cis-, as in oleic acid; if on oppo- Prostaglandins exist in virtually every mammalian tis- site sides, it is trans-, as in elaidic acid, the trans isomer of sue, acting as local hormones; they have important physiologic oleic acid (Figure 21–6). Double bonds in naturally occur- and pharmacologic activities. They are synthesized in vivo ring unsaturated long-chain fatty acids are nearly all in the by cyclization of the center of the carbon chain of 20-carbon cis configuration, the molecules being “bent” 120° at the (eicosanoic) polyunsaturated fatty acids (eg, arachidonic acid) double bond. Thus, oleic acid has a V shape, whereas elaidic to form a cyclopentane ring (Figure 21–3). A related series of acid remains “straight.” Increase in the number of cis double compounds, the thromboxanes, have the cyclopentane ring bonds in a fatty acid leads to a variety of possible spatial con- interrupted with an oxygen atom (oxane ring) (Figure 21–4). figurations of the molecule—for example, arachidonic acid, with Three different eicosanoic fatty acids give rise to three groups of four cis double bonds, is bent into a U shape (Figure 21–7). eicosanoids characterized by the number of double bonds in the This has profound significance for molecular packing in cell side chains (see Figure 23–12), for example, PG1, PG2, and PG3 membranes (see Chapter 40) and on the positions occupied (PG, prostaglandin). Different substituent groups attached to by fatty acids in complex lipids such as phospholipids. Trans the rings give rise to series of prostaglandins and thromboxanes double bonds alter these spatial relationships. Although (TX) labeled A, B, etc (see Figure 23–12)—for example, the “E” double bonds in naturally occurring unsaturated fatty acids type of prostaglandin (as in PGE 2) has a keto group in posi- are almost always in the cis configuration, trans-fatty acids tion 9, whereas the “F” type has a hydroxyl group in this position. are present in foods such as those derived from ruminant fat The leukotrienes and lipoxins (Figure 21–5) are a third group (caused by the action of microorganisms in the rumen) and of eicosanoid derivatives formed via the lipoxygenase pathway those containing partially hydrogenated vegetable oils (industrial (see Figure 23–13). They are characterized by the presence of trans fats), which are a by-product of the saturation of fatty three or four conjugated double bonds, respectively. Leukotrienes cause bronchoconstriction as well as being potent proinflam- 18 matory agents, and play a part in asthma. CH3 CH3 Most Naturally Occurring Unsaturated Trans form Fatty Acids Have cis Double Bonds (elaidic acid) The carbon chains of saturated fatty acids form a zigzag pat- tern when extended at low temperatures (see Figure 21–1). At 120° 10 H H higher temperatures, some bonds rotate, causing chain short- Cis form C C ening, which explains why biomembranes become thinner (oleic acid) C C 9 H H with increases in temperature. Since carbon–carbon double bonds do not allow rotation, a type of geometric isomerism 110° occurs in unsaturated fatty acids, termed cis–trans isomerism, which depends on the orientation of atoms or groups around the axes of their double bonds. If the acyl chains are on the 1 COO– COO– COO– O O FIGURE 21–6 Geometric isomerism of Δ9, 18:1 fatty acids OH (oleic and elaidic acids). There is no rotation around carbon–carbon double bonds. In the cis configuration, the acyl chains are on the FIGURE 21–4 Thromboxane A2 (TXA2). same side of the bond, while in trans form they are on opposite sides.  CHAPTER 21 Lipids of Physiologic Significance 209 –OOC O 1 O CH2 O C R1 2 R2 C O CH O 3 A CH2 O C R2 O sn-1 H2C O C R1 O FIGURE 21–7 Arachidonic acid. Four double bonds in the cis sn-2 R2 C O H configuration bend the molecule into a U shape. C B O sn-3 acids during hydrogenation, or “hardening,” of natural oils in H2 C O C R3 the manufacture of margarine. Dietary trans-fatty acids, how- ever, are now known to be detrimental to health, being associ- FIGURE 21–8 (A) Triacylglycerol. (B) Projection formula ated with increased risk of diseases including cardiovascular showing triacyl-sn-glycerol. disease, diabetes mellitus, and cancer. For this reason the con- tent of industrial trans fats in foods is currently limited to a TRIACYLGLYCEROLS low level by law in many countries. A plan to eliminate these industrially generated fats completely from the world’s food (TRIGLYCERIDES)* ARE THE MAIN supply was announced by the World Health Organization STORAGE FORMS OF FATTY ACIDS in 2018. The triacylglycerols (Figure 21–8) are esters of the trihydric alco- hol glycerol and fatty acids. Mono- and diacylglycerols, wherein Physical and Physiologic Properties one or two fatty acids are esterified with glycerol, are also found in the tissues. These are of particular significance in the synthesis of Fatty Acids Reflect Chain Length & and hydrolysis of triacylglycerols (see Chapters 24 and 25). Degree of Unsaturation The melting points of even-numbered carbon fatty acids Carbons 1 & 3 of Glycerol increase with chain length and decrease according to unsatu- Are Not Identical ration. Thus, a triacylglycerol containing three saturated fatty It is important to realize that carbons 1 and 3 of glycerol are not acids of 12 or more carbons is solid at body temperature, identical when viewed in three dimensions (shown as a projec- whereas if the fatty acid residues are polyunsaturated, it is liq- tion formula in Figure 21–8B). To number the carbon atoms of uid to below 0°C. In practice, natural acylglycerols contain a glycerol unambiguously, the -sn (stereochemical numbering) mixture of fatty acids tailored to suit their functional roles. For system is used. Enzymes readily distinguish between the sn-1 example, membrane lipids, which must be fluid at all environ- and sn-3 positions and are nearly always specific for one or the mental temperatures, are more unsaturated than storage lip- other carbon; for example, glycerol kinase always phosphory- ids. Lipids in tissues that are subject to cooling, for example, lates glycerol on sn-3, not sn-1 to give glycerol-3-phosphate during hibernation or in the extremities of animals, are also and not glycerol-1-phosphate (see Figure 24–2). more unsaturated. ω3 Fatty Acids Are Anti-Inflammatory & Have PHOSPHOLIPIDS ARE THE Health Benefits MAIN LIPID CONSTITUENTS OF Long-chain ω3 fatty acids such as α-linolenic (ALA) (found MEMBRANES in plant oils), eicosapentaenoic (EPA) (found in fish oil), and Many phospholipids are derivatives of phosphatidic acid docosahexaenoic (DHA) (found in fish and algal oils) (see (Figure 21–9), in which a glycerol moiety is esterified to a phos- Table 21–2) have anti-inflammatory effects, perhaps due to phate group and two long-chain fatty acids (glycerophospho- their promotion of the synthesis of less inflammatory prosta- lipids). Phosphatidic acid is important as an intermediate in glandins and leukotrienes as compared to ω6 fatty acids (see the synthesis of triacylglycerols as well as glycerophospholipids Figure 23–12). In view of this, their potential use as a therapy in severe chronic disease where inflammation is a contribu- *According to the standardized terminology of the International tory cause is under intensive investigation. Current evidence Union of Pure and Applied Chemistry and the International Union suggests that diets rich in ω3 fatty acids are beneficial, par- of Biochemistry, the monoglycerides, diglycerides, and triglycer- ticularly for cardiovascular disease, but also for other chronic ides should be designated monoacylglycerols, diacylglycerols, and degenerative diseases such as cancer, rheumatoid arthritis, triacylglycerols, respectively. However, the older terminology is still and Alzheimer disease. widely used, particularly in clinical medicine. 210 SECTION V Metabolism of Lipids O Ceramide 1 O CH2 O C R1 Sphingosine 2 R2 C O CH O OH O 3 CH2 O P O– H CH3 (CH2)12 CH CH CH CH N C R O– CH2 Fatty acid Phosphatidic acid O Phosphoric acid O P O– CH3 + + A O CH2 CH2 N(CH3)3 O CH2 CH2 N CH3 CH3 Choline Choline FIGURE 21–10 A sphingomyelin. + O CH2 CH2NH3 B Phosphatidylcholines (Lecithins) & Ethanolamine Sphingomyelins Are Abundant NH3+ in Cell Membranes C O CH2 CH COO– Glycerophospholipids containing choline (see Figure 21–9), (phosphatidylcholines, commonly called lecithins) are the Serine most abundant phospholipids of the cell membrane and rep- resent a large proportion of the body’s store of choline. Choline OH OH is important in nervous transmission, as acetylcholine, and as 2 3 O H H H a store of labile methyl groups. Dipalmitoyl lecithin is a very 1 4 effective surface-active agent and a major constituent of the D H H OH OH surfactant preventing adherence, due to surface tension, of the 6 5 inner surfaces of the lungs. Its absence from the lungs of prema- OH H ture infants causes respiratory distress syndrome. Most phos- pholipids have a saturated acyl radical in the sn-1 position but Myoinositol an unsaturated radical in the sn-2 position of glycerol. Phosphatidylethanolamine (cephalin) and phospha- O– tidylserine (found in most tissues) are also found in cell CH2 O P O CH2 O membranes and differ from phosphatidylcholine only in that H C OH O O H C O C R3 ethanolamine or serine, respectively, replaces choline (see E Figure 21–9). Phosphatidylserine also plays a role in apoptosis O CH2 R4 C O CH2 (programmed cell death). Sphingomyelins are found in the outer leaflet of the cell membrane lipid bilayer and are particularly abundant in spe- Phosphatidylglycerol cialized areas of the plasma membrane known as lipid rafts FIGURE 21–9 Phospholipids. The —O shown shaded in (see Chapter 40). They are also found in large quantities in the phosphatidic acid is substituted by the substituents A-E to form the myelin sheath that surrounds nerve fibers and play a role in phospholipids: (A) 3-phosphatidylcholine, (B) 3-phosphatidylethanol- cell signaling and in apoptosis. Sphingomyelins contain no amine, (C) 3-phosphatidylserine, (D) 3-phosphatidylinositol, and (E) glycerol, and on hydrolysis they yield a fatty acid, phosphoric cardiolipin (diphosphatidylglycerol). acid, choline, and sphingosine (see Figure 21–10). The com- bination of sphingosine plus fatty acid is known as ceramide (see Figure 24–2) but is not found in any great quantity in (see Chapter 24), a structure also found in the glycosphingo- tissues. Sphingolipids, such as sphingomyelin, in which the lipids (see next section below). phosphate is esterified to sphingosine, a complex amino alco- hol (Figure 21–10), are also important membrane compo- nents. Both glycerophospholipids and sphingolipids have two Phosphatidylinositol Is a Precursor long-chain hydrocarbon tails which are important for their of Second Messengers function in forming the lipid bilayer in cell membranes (see The inositol is present in phosphatidylinositol as the stereo- Chapter 40), but in the former both are fatty acid chains while isomer, myoinositol (see Figure 21–9). Phosphorylated phos- in the latter one is a fatty acid and the second is part of the phatidylinositols (phosphoinositides) are minor components sphingosine molecule (Figure 21–11). of cell membranes, but play an important part in cell signaling  CHAPTER 21 Lipids of Physiologic Significance 211 O O Phosphate O CH2 CH O O O C P + H2 – O CH2CH2N (CH3)3 O Fatty acid tails Glycerol Choline Phosphatidylcholine Phosphate Sphingosine tail OH C O H2 O CH P + O CH2CH2N (CH3)3 NH O– Choline O Fatty acid tail Amide bond A sphingomyelin FIGURE 21–11 Comparison of glycerophospholipid and sphingolipid structures. Both types of phospholipid have two hydrocar- bon tails, in glycerophospholipids both are fatty acid chains (a phosphatidylcholine with one saturated and one unsaturated fatty acid is shown) and in sphingolipids one is a fatty acid chain and the other is part of the sphingosine moiety (a sphingomyelin is shown). The two hydrophobic tails and the polar head group are important for the function of these phospholipids in the lipid bilayer in cell membranes (see Chapter 40). and membrane trafficking. Phosphoinositides may have 1, 2, found in oxidized lipoproteins and has been implicated in or 3 phosphate groups attached to the inositol ring. Phospha- some of their effects in promoting atherosclerosis. tidylinositol 4,5-bisphosphate (PIP2), for example, is cleaved into diacylglycerol and inositol trisphosphate upon stimula- tion by a suitable hormone agonist, and both of these act as Plasmalogens Occur in Brain & Muscle internal signals or second messengers. These compounds constitute as much as 10 to 30% of the phospholipids of brain and heart. Structurally, the plasmalo- gens resemble phosphatidylethanolamine but possess an Cardiolipin Is a Major Lipid of ether link on the sn-1 carbon instead of the ester link found Mitochondrial Membranes in acylglycerols. Typically, the alkyl radical is an unsaturated Phosphatidic acid is a precursor of phosphatidylglycerol, alcohol (Figure 21–13). In some instances, choline, serine, or which in turn gives rise to cardiolipin (see Figure 21–9). This inositol may be substituted for ethanolamine. Plasmalogens phospholipid is found only in mitochondria and is essential play an important role in the structure of membranes, and are for the mitochondrial function. Decreased cardiolipin levels or believed to be involved in cell signaling and to act as endog- alterations in its structure or metabolism cause mitochondrial enous antioxidants. dysfunction in aging and in pathologic conditions including heart failure, cancer, and Barth syndrome (a rare genetic dis- ease causing cardioskeletal myopathy). O 1 CH2 O C R Lysophospholipids Are Intermediates HO 2 CH O CH3 + in the Metabolism of Phosphoglycerols 3 CH2 O P O CH2 CH2 N CH3 O– CH3 These are glycerophospholipids containing only one acyl radical, for example, lysophosphatidylcholine (lysolecithin) Choline (Figure 21–12), which is important in the metabolism and interconversion of phospholipids. This compound is also FIGURE 21–12 Lysophosphatidylcholine (lysolecithin). 212 SECTION V Metabolism of Lipids O 1 CH2 O CH CH R1 Ceramide Glucose Galactose N-Acetylgalactosamine (Acyl- 2 sphingo- R2 C O CH O NeuAc Galactose sine) 3 CH2 O P O CH2 CH2 NH3+ or O– Cer Glc Gal GalNAc Gal Ethanolamine NeuAc FIGURE 21–13 Plasmalogen. FIGURE 21–15 GM1 ganglioside, a monosialoganglioside, the receptor in human intestine for cholera toxin. GLYCOLIPIDS (GLYCOSPHINGOLIPIDS) ARE toxin. The simplest ganglioside found in tissues is GM3 (see Figure 24–8), which contains ceramide, one molecule of glu- IMPORTANT IN NERVE TISSUES & cose, one molecule of galactose, and one molecule of NeuAc. IN THE CELL MEMBRANE In the shorthand nomenclature used, G represents ganglio- Glycolipids are lipids with an attached carbohydrate or car- side; M is a monosialo-containing species; and 3 is a number bohydrate chain. They are widely distributed in every tissue assigned on the basis of chromatographic migration. GM1 of the body, particularly in nervous tissue such as brain. They (Figure 21–15), a more complex ganglioside derived from occur particularly in the outer leaflet of the plasma membrane, GM3, is of considerable biologic interest, as it is known to be where they contribute to cell surface carbohydrates which the receptor in human intestine for cholera toxin. Other gan- form the glycocalyx (see Chapter 15). gliosides can contain anywhere from one to five molecules of The major glycolipids found in animal tissues are glyco- sialic acid, giving rise to di-, trisialogangliosides, etc. sphingolipids. They contain ceramide and one or more sugars. Galactosylceramide (Figure 21–14) is a major glycosphingo- STEROIDS PLAY MANY lipid of brain and other nervous tissue, found in relatively low PHYSIOLOGICALLY amounts elsewhere. It contains a number of characteristic C24 fatty acids, for example, cerebronic acid. IMPORTANT ROLES Galactosylceramide can be converted to sulfogalacto- Although cholesterol is probably best known by most people sylceramide (sulfatide) which has a sulfo group attached to for its association with atherosclerosis and heart disease, it has the O in the three position of galactose and is present in high many essential roles in the body (see Chapter 26). It is the precur- amounts in myelin. Glucosylceramide resembles galactosyl- sor of a large number of equally important steroids that include ceramide, but the head group is glucose rather than galactose. the bile acids, adrenocortical hormones, sex hormones, It is the predominant simple glycosphingolipid of extraneural vitamin D (see Chapters 26, 41, 44), and cardiac glycosides. tissues, also occurring in the brain in small amounts. Ganglio- All steroids have a similar cyclic nucleus resembling phen- sides are complex glycosphingolipids derived from glucosyl- anthrene (rings A, B, and C) to which a cyclopentane ring (D) ceramide that contain in addition one or more molecules of is attached. The carbon positions on the steroid nucleus are sialic acid. Neuraminic acid (NeuAc; see Chapter 15) is the numbered as shown in Figure 21–16. It is important to real- principal sialic acid found in human tissues. Gangliosides are ize that in structural formulas of steroids, a simple hexagonal also present in nervous tissues in high concentration. They ring denotes a completely saturated six-carbon ring with all function in cell–cell recognition and communication and as valences satisfied by hydrogen bonds unless shown otherwise; receptors for hormones and bacterial toxins such as cholera that is, it is not a benzene ring. All double bonds are shown as such. Methyl groups (shown as single bonds unattached at the Ceramide farther [methyl] end) occur typically at positions 10 and 13 Sphingosine and constitute C atoms 19 and 18. A side chain at position 17 is usual (as in cholesterol). If the compound has one or more OH O hydroxyl groups and no carbonyl or carboxyl groups, it is a H CH3 (CH2 ) 12 CH CH CH CH N C CH(OH) (CH 2 ) 21 CH 3 sterol, and the name terminates in -ol. CH 2 OH Fatty acid 18 12 17 O (eg, cerebronic acid) 11 16 HO H 19 13 Galactose O CH2 1 C D 9 15 14 H OR H H 2 10 8 A B 3 3 7 5 H OH 4 6 FIGURE 21–14 Structure of galactosylceramide. FIGURE 21–16 The steroid nucleus.  CHAPTER 21 Lipids of Physiologic Significance 213 17 “Chair” form “Boat” form 3 FIGURE 21–17 Conformations of stereoisomers of the ste- HO 5 6 roid nucleus. Because of Asymmetry in the Steroid FIGURE 21–19 Cholesterol. Molecule, Many Stereoisomers Ergosterol Is a Precursor of Vitamin D Are Possible Ergosterol occurs in plants and yeast and is important as a Each of the six-carbon rings of the steroid nucleus is capable dietary source of vitamin D (see Chapter 44) (Figure 21–20). of existing in the three-dimensional conformation either of a When irradiated with ultraviolet light in the skin, ring B is “chair” or a “boat” (Figure 21–17). In naturally occurring ste- opened to form vitamin D2 in a process similar to the one that roids, virtually all the rings are in the “chair” form, which is forms vitamin D3 from 7-dehydrocholesterol in the skin (see the more stable conformation. With respect to each other, the Figure 44–3). rings can be either cis or trans (Figure 21–18). The junction between the A and B rings may be cis or trans in naturally occurring steroids. The junction between B and C is trans, Polyprenoids Share the Same Parent as is usually the C/D junction. Bonds attaching substituent Compound as Cholesterol groups above the plane of the rings (β bonds) are shown with Polyprenoids are not steroids but are related to them because bold solid lines, whereas those bonds attaching groups below they are synthesized, like cholesterol (see Figure 26–2), from (α bonds) are indicated with broken lines. The A ring of a 5α five-carbon isoprene units (Figure 21–21). They include ubi- steroid (ie, the hydrogen at position 5 is in the α configuration) quinone (see Chapter 13), which participates in the respi- is always trans to the B ring, whereas it is cis in a 5β steroid ratory chain in mitochondria, and dolichols, long-chain (ie, the hydrogen at position 5 is in the β configuration). The alcohols containing 15 to 23 isoprene units in animal cells methyl groups attached to C10 and C13 are invariably in the (Figure 21–22), which take part in glycoprotein synthesis by β configuration. transferring oligosaccharide residues to asparagine residues of the glycoprotein polypeptide chains as they are formed (see Cholesterol Is a Significant Constituent Chapter 46). Plant-derived polyprenoids include rubber, cam- of Many Tissues phor, the fat-soluble vitamins A, D, E, and K, and β-carotene (provitamin A). Cholesterol (Figure 21–19) is widely distributed in all cells of the body but particularly in nervous tissue. It is a major constituent of the plasma membrane (see Chapter 40) and of plasma lipoproteins (see Chapters 25 and 26). It is often found LIPID PEROXIDATION IS A as cholesteryl ester, where the hydroxyl group on position 3 is SOURCE OF FREE RADICALS esterified with a long-chain fatty acid. It occurs in animals but Peroxidation (auto-oxidation) of lipids exposed to oxygen- not in plants or bacteria. forming peroxides is responsible not only for deterioration of foods (rancidity), but also for damage to tissues in vivo, A where it may be a cause of cancer, inflammatory diseases, B H 13 H 10 atherosclerosis, and aging. The deleterious effects are con- D sidered to be caused by free radicals, molecules that have B 10 C 5 9 8 14 unpaired valence electrons, making them highly reactive. B A A Free radicals containing oxygen (eg, ROO , RO , OH ) are termed 3 5 H H 3 H or or C 17 13 D 1 9 H 1 14 10 H 8 H 10 A 5 B A 5 B 3 H 3 H B FIGURE 21–18 Generalized steroid nucleus, showing (A) an HO all-trans configuration between adjacent rings and (B) a cis con- figuration between rings A and B. FIGURE 21–20 Ergosterol. 214 SECTION V Metabolism of Lipids CH3 CH C CH CH CH2OH FIGURE 21–21 Isoprene unit. n FIGURE 21–22 Dolichol. Major dolichols in humans contain 19 reactive oxygen species (ROS). These are produced during or 20 isoprene units. peroxide formation from fatty acids containing methylene- interrupted double bonds, that is, those found in the naturally occurring polyunsaturated fatty acids (Figure 21–23). Lipid Antioxidants are used to control and reduce lipid per- peroxidation is a chain reaction in which free radicals oxidation, both by humans in their activities and in nature. formed in the initiation stage in turn generate more (prop- Propyl gallate, butylated hydroxyanisole (BHA), and butyl- agation), and thus it has potentially devastating effects. The ated hydroxytoluene (BHT) are antioxidants used as food processes of initiation and propagation can be depicted as additives. Naturally occurring antioxidants include vitamin E follows: (tocopherol) (see Chapter 44), which is lipid soluble, and urate and vitamin C, which are water soluble. β-Carotene is 1. Initiation: A free radical (X ) reacts with a polyunsaturated an antioxidant at low PO2. Antioxidants fall into two classes: fatty acid forming the first fatty acid radical (R 1). (1) preventive antioxidants, which reduce the rate of chain ini- X + R1H → R 1 + XH tiation (stage 1 above) and (2) chain-breaking antioxidants, which interfere with chain propagation (stage 2 above). Pre- 2. Propagation: The unstable fatty acid radical R 1 reacts with ventive antioxidants include catalase and other peroxidases oxygen to produce a peroxyl radical (R1OO ) which then such as glutathione peroxidase (see Figure 20–3) that react attacks another fatty acid to form a new fatty acid radical R 2 with ROOH; selenium, which is an essential component of and a peroxide of R1. R 2 can then react with fatty acid R3H glutathione peroxidase and regulates its activity, and chelators and so on in a chain reaction. Thus one free radical may be of metal ions such as ethylenediaminetetraacetate (EDTA) and responsible for the peroxidation of a very large number of diethylenetriaminepentaacetate (DTPA). In vivo, the principal polyunsaturated fatty acid molecules. chain-breaking antioxidants are superoxide dismutase, which R 1 + O2 → R1OO acts in the aqueous phase to trap superoxide free radicals R1OO + R2H → R1OOH + R 2, etc. (O2– ), urate, and vitamin E, which acts in the lipid phase to trap ROO radicals. The process may be terminated at the third stage. Peroxidation is also catalyzed in vivo by heme compounds 3. Termination: The chain reaction terminates when two and by lipoxygenases (see Figure 23–13) found in platelets radicals react to form a non-radical product (ROOR and leukocytes. Other products of auto-oxidation or enzy- or RR). mic oxidation of physiologic significance include oxysterols (formed from cholesterol) and the prostaglandin-like iso- ROO + ROO → ROOR + O2 prostanes (formed from the peroxidation of polyunsaturated ROO + R → ROOR fatty acids such as arachidonic acid) which are used as reliable R + R → RR markers of oxidative stress in humans. FIGURE 21–23 Lipid peroxidation. The reaction may be initiated by an existing free radical (X ), by light, or by metal ions. Malondialde- hyde is only formed by fatty acids with three or more double bonds and is used as a measure of lipid peroxidation together with ethane from the terminal two carbons of ω3 fatty acids and pentane from the terminal five carbons of ω6 fatty acids.  CHAPTER 21 Lipids of Physiologic Significance 215 Amphipathic lipid A Polar or hydrophiIic groups Nonpolar or hydrophobic groups Aqueous phase Aqueous phase Aqueous phase “Oil” or nonpolar phase Nonpolar phase “Oil” or nonpolar phase Aqueous phase Lipid bilayer Oil in water emulsion Micelle B D C Nonpolar phase Aqueous Aqueous phase phase Lipid Aqueous Lipid bilayer compartments bilayers Liposome Liposome (Unilamellar) (Multilamellar) E F FIGURE 21–24 Formation of lipid membranes, micelles, emulsions, and liposomes from amphipathic lipids, for example, phospholipids. AMPHIPATHIC LIPIDS in which the hydrophobic tails of the molecules are inside SELF-ORIENT AT OIL: while the hydrophilic heads face the water. Liposomes consist of spheres of lipid bilayers that enclose part of the WATER INTERFACES aqueous medium. They may be formed by sonicating an amphipathic lipid in an aqueous medium. Aggregation of They Form Membranes, Micelles, bile salts into micelles and the formation of mixed micelles Liposomes, & Emulsions with the products of fat digestion are important in facili- In general, lipids are insoluble in water since they contain tating absorption of lipids from the intestine. Liposomes a predominance of nonpolar (hydrocarbon) groups. How- are of potential clinical use—particularly when combined ever, fatty acids, phospholipids, sphingolipids, bile salts, with tissue-specific antibodies—as carriers of drugs in the and, to a lesser extent, cholesterol, contain polar groups. circulation, targeted to specific organs, for example, in Therefore, a part of the molecule is hydrophobic, or water cancer therapy. In addition, they are used for gene trans- insoluble, and a part is hydrophilic, or water soluble. Such fer into vascular cells and as carriers for topical and trans- molecules are described as amphipathic (Figure 21–24). dermal delivery of drugs and cosmetics. Emulsions are They become oriented at oil–water interfaces with the much larger particles, formed usually by nonpolar lipids polar group in the water phase and the nonpolar group in in an aqueous medium. These are stabilized by emulsify- the oil phase. A bilayer of such amphipathic lipids is the ing agents such as amphipathic lipids (eg, phosphatidyl- basic structure in biologic membranes (see Chapter 40). choline), which form a surface layer separating the main When a critical concentration of these lipids is present in bulk of the nonpolar material from the aqueous phase (see an aqueous medium, they form micelles, spherical particles Figure 21–24). 216 SECTION V Metabolism of Lipids constituents of membranes and the outer layer of lipoproteins, SUMMARY as surfactant in the lung, as precursors of second messengers, Lipids have the common property of being relatively insoluble and as constituents of nervous tissue. in water (hydrophobic) but soluble in nonpolar solvents. Glycolipids are also important constituents of nervous tissue Amphipathic lipids also contain one or more polar groups, such as brain and the outer leaflet of the cell membrane, making them suitable as constituents of membranes at lipid- where they contribute to the carbohydrates on the cell water interfaces. surface. Lipids of major physiologic significance include fatty acids and Cholesterol, an amphipathic lipid, is an important component their esters, together with cholesterol and other steroids. of membranes. It is the parent molecule from which all other Long-chain fatty acids may be saturated, monounsaturated, steroids in the body, including major hormones such as the or polyunsaturated, according to the number of double adrenocortical and sex hormones, D vitamins, and bile acids, bonds present. Their fluidity decreases with chain length and are synthesized. increases according to degree of unsaturation. Peroxidation of lipids containing polyunsaturated fatty acids Eicosanoids are formed from 20-carbon polyunsaturated fatty leads to generation of free radicals that damage tissues and acids and make up an important group of physiologically and cause disease. pharmacologically active compounds known as prostaglandins, thromboxanes, leukotrienes, and lipoxins. The esters of glycerol are quantitatively the most significant REFERENCES lipids, represented by triacylglycerol (“fat”), a major constituent Eljamil AS: Lipid Biochemistry: For Medical Sciences. iUniverse, of some lipoprotein classes and the storage form of lipid 2015. in adipose tissue. Glycerophospholipids and sphingolipids Gurr MI, Harwood JL, Frayn KN, et al: Lipids, Biochemistry, are amphipathic lipids and have important roles—as major Biotechnology and Health. Wiley-Blackwell, 2016.