Fatty Acids

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Fatty Acids

  1. 1. Fatty Acids: Structures and Introductory article Properties . Introduction Article Contents Arild C Rustan, University of Oslo, Oslo, Norway . Overview of Fatty Acid Structure Christian A Drevon, University of Oslo, Oslo, Norway . Major Fatty Acids . Properties of Fatty Acids . Requirements/Uses of Fatty Acids in Human Nutrition Fatty acids play a key role in metabolism: as a metabolic fuel, as a necessary component of . Uses of Fatty Acids in the Pharmaceutical/Personal all membranes and as a gene regulator. In addition, fatty acids have a number of industrial Hygiene Industries uses. Introduction Saturated fatty acids Fatty acids, both free and as part of complex lipids, play a number of key roles in metabolism – as a major metabolic Saturated fatty acids are ‘filled’ (saturated) with hydrogen. fuel (storage and transport of energy), as essential Most saturated fatty acids are straight hydrocarbon chains components of all membranes and as gene regulators with an even number of carbon atoms. The most common (Table 1). In addition, dietary lipids provide polyunsatu- fatty acids contain 12–22 carbon atoms. rated fatty acids (PUFAs) that are precursors of powerful locally acting metabolites, i.e. the eicosanoids. As part of complex lipids, fatty acids are also important for thermal Unsaturated fatty acids and electrical insulation, and for mechanical protection. Moreover, free fatty acids and their salts may function as Monounsaturated fatty acids have one double bond that detergents and soaps owing to their amphiphatic proper- can occur in different positions. The most common ties and formation of micelles. monoenes have a chain length of 16–22 and a double bond with the cis configuration. This means that the hydrogen atoms on either side of the double bond are oriented in the same direction. Often the cis bond is found at D9–10. Trans isomers may be produced during Overview of Fatty Acid Structure industrial processing (hydrogenation) of unsaturated oils and in the gastrointestinal tract of ruminants. The presence Fatty acids are carbon chains with a methyl group at one of a double bond causes restriction in the motion of the acyl end of the molecule (represented by omega, o) and a chain at that point. The cis configuration gives a kink in the carboxyl group at the other end (Figure 1). The carbon atom molecular shape and cis fatty acids are thermodynamically next to the carboxyl group is called the a carbon. The letter less stable than the trans forms. The cis fatty acids have n is also often used instead of the Greek o to represent the lower melting point than the trans fatty acids or their methyl end. The systematic nomenclature for fatty acids saturated counterparts. where the locations of double bonds are indicated with In polyunsaturated fatty acids (PUFAs) the first double reference to the carboxyl group (D) is also commonly used. bond may be found between the third and the fourth Figure 2 outlines the structures of different types of carbon atom from the o carbon; these are called o-3 fatty naturally occurring fatty acids. acids. If the first double bond is between the sixth and seventh carbon atom, then they are called o-6 fatty acids. The double bonds in PUFAs are separated from each other Table 1 Functions of fatty acids by a methylene group. Energy – high, low weight/energy unit PUFAs, which are produced only by plants and Transport form of energy – blood lipids (triacylglycerol in phytoplankton, are essential to all higher organisms, lipoproteins) Storage of energy – adipose tissue (obesity) CH3 – (CH2)n – CH2 – CH2 – COOH ω β α Component of cell membranes (phospholipids) Isolation – thermal, electrical and mechanical Figure 1 Nomenclature for fatty acids. Fatty acids may be named Signals – eicosanoids, gene regulation (transcription) according to systematic or trivial nomenclature. One systematic way to describe fatty acids is related to the methyl (o) end. This is used to describe the position of double bonds from the end of the fatty acid. The letter n is also often used to describe the o position of double bonds. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1
  2. 2. Fatty Acids: Structures and Properties ω-characteristic Methyl end Carboxyl end Saturation ∆-characteristics Stearic acid 18:0 COOH Saturate 18:0 9 9 Oleic acid 18:1, ω-9 COOH Monoene 18:1 ∆ 9 6 12 9 Linoleic 18:2, ω-6 COOH Polyene 18:2 ∆ 9,12 3 15 12 9 α-Linolenic 18:3, ω-3 COOH Polyene 18:3 ∆ 9,12,15 3 17 14 11 8 5 EPA 20:5, ω-3 COOH Polyene 20:5 ∆ 5, 8,11,14,17 3 19 16 13 10 7 4 DHA 22:6, ω-3 COOH Polyene 22:6 ∆ 4,7,10,13,16,19 Figure 2 Structure of different unbranched fatty acids with a methyl end and an acidic end. Stearic acid is a trivial name for a saturated fatty acid with 18 carbon atoms (18:0). Oleic acid has 18 carbon atoms and one double bond in the o-9 position (18:1, o-9), whereas eicosapentaenoic acid is shortened (20:5, o-3). This is the most common systematic nomenclature used. It is also possible to describe fatty acids systematically related to the acidic end of the fatty acids; called D (delta, from the Greek). All unsaturated fatty acids are shown with cis configuration of the double bonds. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid. including mammals. o-3 and o-6 fatty acids cannot be Major Fatty Acids interconverted, and both are essential nutrients. PUFAs are further metabolized in the body by addition of carbon The most common saturated fatty acid in animals, plants atoms and desaturation (extraction of hydrogen). Mam- and microorganisms is palmitic acid (16:0). Stearic acid mals have desaturases that are capable of removing (18:0) is a major fatty acid in animals and some fungi, and a hydrogens only from carbon atoms between an existing minor component in most plants. Myristic acid (14:0) has a double bond and the carboxyl group (Figure 3). b Oxidation widespread occurrence, occasionally as a major compo- of fatty acids may take place in either mitochondria or nent. Shorter-chain saturated acids with 8–10 carbon peroxisomes. atoms are found in milk triacylglycerol. Oleic acid (18:1, o-9) is the most common monoenoic fatty acid in plants and animals. It is also found in microorganisms. Palmitoleic acid (16:1, o-7) also occurs widely in animals, plants and microorganisms, and is a major component in some seed oils. ω-6 Fatty acids Enzymes ω-3 Fatty acids Linoleic acid (18:2, o-6) is a major fatty acid in plant Linoleic 18:2 α-Linolenic 18:3 lipids. In animals it is derived only from dietary vegetables, ∆ 6-desaturase plants and marine oils. Arachidonic acid (20:4, o-6) is a γ-Linolenic 18:3 Octadecatetraenoic 18:4 major component of animal phospholipids. It is also a elongase major component of marine algae and some terrestrial Dihomo-γ-linolenic 20:3 Eicosatetraenoic 20:4 species, but very little is found in the diet. a-Linolenic acid ∆ 5-desaturase (18:3, o-3) is found in higher plants and algae. Eicosa- Arachidonic 20:4 Eicosapentaenoic 20:5 pentaenoic acid (EPA; 20:5, o-3) and docosahexaenoic elongase acid (DHA; 22:6, o-3) are major fatty acids of marine Adrenic 22:4 Docosapentaenoic 22:5 algae, fish and fish oils. These fatty acids are found in elongase animals, especially in phospholipids in the brain, retina Tetracosatetraenoic 24:4 Tetracosapentaenoic 24:5 and testes. ∆ 6-desaturase Tetracosapentaenoic 24:5 Tetracosahexaenoic 24:6 β-oxidation Docosapentaenoic 22:5 Docosahexaenoic 22:6 Properties of Fatty Acids Physical properties Figure 3 Synthesis of o-3 and o-6 polyunsaturated fatty acids (PUFAs). There are two families of essential fatty acids that are metabolized in the The short-chain fatty acids with chain lengths up to eight body as shown in this figure. Retroconversion, e.g. DHA!EPA also takes carbon atoms are poorly water-soluble, but they are place. present in low concentrations. The actual solubility, 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
  3. 3. Fatty Acids: Structures and Properties particularly of longer-chain acids, is often very difficult to Platelets White Chemotactic determine since it is markedly influenced by pH, and also blood cell agent ω-3 ω-3 because fatty acids have a tendency to associate, leading to Eicosanoids the formation of monolayers or micelles. Formation of micelles in aqueous solutions of lipids is associated with Substrate specificity CH3 COOH very rapid changes in physical properties over a limited CH3 COOH range of concentration. The point of change is known as Lipid peroxidation the critical micellar concentration (CMC), and exemplifies the tendency of lipids to self-associate rather than remain Red blood cells Membrane flexibility more flexible cell as single molecules. The CMC is not a fixed value, but is a small concentration range that is markedly affected by the presence of other ions, neutral molecules, etc. Acylation of proteins Protein Fatty acid Fatty acids are easily extracted with non-polar solvents Membrane from solutions or suspensions by lowering the pH to form Transcription factors the uncharged carboxyl group. In contrast, raising the pH increases solubility because of the formation of alkali metal Nucleus Fatty acid mRNA salts, which are familiar as soaps. Soaps have important DNA properties as association colloids and are surface-active Protein agents. Promoter The influence of fatty acid structure on its melting point is that branched chains and cis double bonds will lower the Figure 4 Mechanisms of action for fatty acids. Thromboxanes formed in blood platelets promote aggregation (clumping) of blood platelets. melting point compared with equivalent saturated chains. Leucotrienes in white blood cells act as chemotactic agents (attracting In addition, the melting point of a fatty acid depends on other white blood cells). See Figure 6. whether the chain is even- or odd-numbered; the latter increases the melting point. are mostly formed in cells where they execute their effects, Saturated fatty acids are very stable, whereas unsatu- and they are rapidly formed and degraded. Different cell rated acids are susceptible to oxidation: the more double types produce different types of eicosanoids with different bonds, the greater the susceptibility. Unsaturated fatty biological functions. For example, platelets mostly make acids, therefore, should be handled under an atmosphere of thromboxanes, whereas endothelial cells mainly produce inert gas and kept away from oxidants and compounds prostacyclins. Eicosanoids from the o-3 PUFA are usually that give rise to free radicals. Antioxidants may be very less potent than eicosanoids derived from the o-6 fatty important in the prevention of potentially harmful attacks acids (Figure 6). on acyl chains in vivo (see later). For most chemical reactions, fatty acids have to be Substrate specificity ‘activated’ by forming thiol esters. The active form of fatty acids is usually the thiol ester with the complex nucleotide The activities of fatty acids may be dependent on their coenzyme A (CoA), which also makes the acyl chains having a higher or lower ability to interact with enzymes or water-soluble. The acyl–CoA molecules can, for example, receptors, as compared with other fatty acids. For be used for oxidation and esterification. example, EPA is a poorer substrate than all other examined fatty acids for esterification to cholesterol and diacylgly- cerol. Some o-3 fatty acids are preferred substrates for Biological effects certain desaturases. The preferential incorporation of o-3 fatty acids into some phospholipids occurs because o-3 The different mechanisms by which fatty acids can influence biological systems are outlined in Figure 4. fatty acids are preferred substrates for the enzymes responsible for phospholipid synthesis. These examples of altered substrate specificity of o-3 PUFA for certain Eicosanoids enzymes illustrate why EPA and DHA are mostly found in Eikosa means 20 in Greek, and denotes the number of certain phospholipids. carbon atoms in the polyunsaturated fatty acids that act as precursors of eicosanoids (Figure 5). These signal mole- Membrane fluidity cules, which are formed in several different ways, are called When large amounts of very long-chain o-3 fatty acids are leucotrienes, prostaglandins, thromboxanes, prostacy- ingested, there is a high incorporation of EPA and DHA in clins, lipoxins and hydroxy fatty acids. Eicosanoids are membrane phospholipids. An increased amount of o-3 important for several cellular functions such as platelet PUFA may alter the physical characteristics of the aggregability (ability to clump and fuse), chemotaxis membranes. Altered fluidity may lead to changes of (movement of blood cells) and cell growth. Eicosanoids membrane protein functions. The very large amount of ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3
  4. 4. Fatty Acids: Structures and Properties AA (EPA) in phospholipid / diacylglycerol 5-Lipoxygenase 12-Lipoxygenase Leucotriene LTA (LTA ) 4 5 Arachidonic acid (EPA) 12-OH -acids Cyclooxygenase (COX) Cyclic endoperoxides Different enzymes LTC4 (LTC5) LTB4 (LTB5) LTD4 (LTD5) Prostaglandin Prostacyclin Thromboxane LTE 4 (LTE5 ) PGE2 (PGE3) PGI2 (PGI3) TXA2 (TXA3 ) Figure 5 Synthesis of eicosanoids from arachidonic acid (AA) or eicosapentaenoic acid (EPA). Fatty acid AA EPA AA EPA AA EPA low-density lipoproteins (LDL). Modified LDL might be endocytosed by macrophages and initiate development of Enzyme Cyclooxygenase Lipoxygenase atherosclerosis. Oxidatively modified LDL has been found Cell type Platelets Endothelial cells Leucocytes in atherosclerotic lesions, and LDL rich in oleic acid was found to be more resistant to oxidative modification than Eicosanoids TXA2 TXA3 PGI2 PGI3 LTB4 LTB5 LDL enriched with o-6 fatty acids in rabbits. Although some of the published data are conflicting, several of the Biological effect well-performed studies indicate small or no harmful effects Aggregation +++ + of o-3 fatty acids. From epidemiological studies it should Antiaggregation +++ +++ be recalled that the dietary intake of saturated fatty acids, Vasoconstriction +++ Vasodilatation +++ +++ trans fatty acids and cholesterol is strongly correlated to Chemotaxis +++ + development of coronary heart diseases, whereas intake of PUFA is related to reduced incidence of coronary heart Figure 6 Biological effects of eicosanoids derived from arachidonic acid diseases. Several studies suggest it is important that the (AA; 20:4, o-6) or eicosapentaenoic acid (EPA; 20:5, o-3). proper amount of antioxidants is included in the diet with the PUFA to decrease the risk of lipid peroxidation. DHA in phosphatidylethanolamine and phosphatidylser- Acylation of proteins ine in certain areas of the retinal rod outer segments is Some proteins are acylated with stearic (18:0), palmitic probably crucial for the function of membrane phospho- (16:0) or myristic acid (14:0). This acylation of proteins is lipids in light transduction, since these lipids are located important for anchoring certain proteins in membranes or close to the rhodopsin molecules. It has been shown that folding of the proteins, and is crucial for the function of the flexibility of membranes from blood cells in animals fed these proteins. Although the saturated fatty acids are most fish oil is markedly increased, and this might be important commonly covalently linked to proteins, PUFA may also for the microcirculation. Increased incorporation of very acylate proteins. long-chain o-3 PUFA into plasma lipoproteins changes the physical properties of low-density lipoproteins (LDL), lowering the melting point of core cholesteryl esters. Gene interactions Fatty acids or their derivatives (acyl–CoA or eicosanoids) may interact with nuclear receptor proteins that bind to Lipid peroxidation certain regulatory regions of DNA and thereby alter Lipid peroxidation products may act as biological signals. transcription of these genes (Figure 4). The receptor protein One of the major concerns with intake of PUFAs has been may act in combination with a fatty acid functioning as a their high degree of unsaturation, and therefore the transcription factor. The first example of this was the possibility that they might promote the peroxidation of peroxisome proliferator-activated receptor (PPAR). Nat- 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
  5. 5. Fatty Acids: Structures and Properties ural fatty acids are weak activators of PPAR, and this may (mainly linoleic acid, 18:2, o-6) have also been shown to be explained by the rapid oxidation of fatty acids. If fatty have many beneficial effects with respect to cardiovascular acids are blocked from being b-oxidized, they are much diseases (Table 3). more potent stimulators of PPAR than natural fatty acids. Fatty acids may also influence expression of several glycolytic and lipogenic genes independent of PPAR. It has been demonstrated that one eicosanoid derived from Requirements/Uses of Fatty Acids in arachidonic acid, prostaglandin J2 (PGJ2), binds to PPARg, which is an important transcription factor in adipose tissue Human Nutrition and colon. Fatty acids as well as eicosanoids can bind directly to PPARa and PPARg. PUFA may also influence Although the data we have on the required intake of proliferation of white blood cells, together with the cells, essential fatty acids are relatively few, the adequate intakes tendency to die by programmed cell death (apoptosis) or of linoleic acid (18:2, o-6) and a-linolenic acid (18:3, o-3) necrosis. Thus, fatty acids may be important for regulation should be 2% and 1% of total energy, respectively (Table 4). of gene transcription and thereby regulate metabolism, cell Present knowledge suggests that 0.2–0.3% of the energy proliferation and cell death. should be derived from preformed very long-chain o-3 PUFAs (EPA and DHA) to avoid signs or symptoms of deficiency. This corresponds to approximately half a gram Metabolic effects of these o-3 fatty acids per day. It should be stressed that this is the minimum intake to avoid clinical symptoms of Replacement of saturated fat with monounsaturated and deficiency. From many epidemiological and experimental polyunsaturated fat (especially o-6 PUFA) decreases the studies there is relatively strong evidence that there are plasma concentration of total and LDL cholesterol significant beneficial effects of additional intake of PUFA (Table 2). The mechanism for these effects is an increased in general and very long-chain o-3 fatty acids (EPA and uptake of LDL particles from the circulation by the liver. DHA) in particular. It is possible that the beneficial effects Dietary very long-chain o-3 fatty acids (EPA and DHA) may be obtained at intakes as low as one to two fish meals decrease plasma triacylglycerol levels by reducing produc- weekly, but many of the measurable effects on risk factors tion of triacylglycerol-rich lipoproteins. In addition to are observed at intakes of 1–2 g day 2 1 of very long-chain effects on plasma lipids, dietary fatty acids can influence o-3 PUFA. If 1–2 g day 2 1 of EPA and DHA is consumed metabolic and cardiovascular events in numerous ways, as in combination with proper amounts of fruits and shown in Table 3. For instance, saturated fat may negatively vegetables, and limited amounts of saturated and trans affect several factors related to cardiovascular diseases and fatty acids, most people will probably benefit with better atherosclerosis, whereas very long-chain o-3 PUFAs have health for a longer time (Figure 7). been shown to exert a number of beneficial effects upon the cardiovascular system. Briefly, o-3 PUFAs decrease platelet and leucocyte reactivity, inhibit lymphocyte proliferation, and may slightly decrease blood pressure. Uses of Fatty Acids in the o-3 PUFAs may also beneficially influence vessel wall characteristics and blood rheology, prevent ventricular Pharmaceutical/Personal Hygiene arrhythmias and improve insulin sensitivity. o-6 PUFAs Industries There are three different principles that justify the use of Table 2 Effect of fatty acids on plasma and LDL cholesterol fatty acids (or fatty acids as part of complex lipids) as ingredients in pharmaceutical products. The formal DCholesterol DLDL cholester- distinction between these three principles is explained by (mmol L 2 1) ol (mmol L 2 1) the following definitions: 12:0 1 0.03 1 0.03 14:0 1 0.12 1 0.14 . excipients – these are physiologically inactive ingredi- 16:0 1 0.05 1 0.04 ents in pharmaceuticals that enable delivery of medicines TransMarin 1 0.035 1 0.04 in a variety of dosage forms; TransVeg 1 0.026 1 0.037 . pharmaceutical formulation – a drug is an active 18:1 2 0.003 2 0.006 compound in a pharmaceutical formulation; and 18:2/3 2 0.015 2 0.015 . active ingredient – fatty acids may be used as active ingredients, i.e. as physiologically active drug sub- TransMarin, trans fatty acids of marine origin; transVeg, trans fatty stances. acids of vegetable origin. Personal communication from Jan I. Pedersen, University of Oslo. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5
  6. 6. Fatty Acids: Structures and Properties Table 3 Dietary fatty acids may influence metabolic and cardiovascular events Event Negative influence Positive influence Coronary artery disease Saturated o-3 PUFA and monoenes Stroke Saturated ? Blood pressure Saturated o-3 PUFA Insulin resistance Saturated o-3 PUFA Blood clotting and fibrinolysis ? o-3 PUFA (?) and o-6 PUFA (?) Function of platelets ? o-3 PUFA and o-6 PUFA (?) Hyperlipidaemia Saturated o-3 PUFA, o-6 PUFA and monoenes Oxidation of LDL o-6 PUFA (?) Monoenes Atherogenesis (leucocyte reactivity, Saturated and monoenes (?) o-3 PUFA and o-6 PUFA immunological functions) Endothelial dysfunction ? o-3 PUFA (?) Cardiac arrhythmias Saturated o-3 PUFA and o-6 PUFA o-3 PUFAs, very long-chain o-3 fatty acids (EPA and DHA); o-6, mainly linoleic acid (18:2, o-6); monoenes, oleic acid (cis 18:1, o-9); saturated fatty acids, mainly myristic and palmitic acid (14:0 and 16:0). Table 4 Suggested intake of essential PUFA Intake o-3 (% of energy) o-6 (% of energy) o-3 (mg day 2 1) o-6 (mg day 2 1) Minimum 0.2–0.3 1–3 400–600 2400–7200 Optimum 1–2 3–7.5a 2400–4800 7200–18 000 a Pregnant and breastfeeding women. The numbers are based on data from patients with essential fatty acid deficiency and on estimation of required and optimal intake in healthy, normal individuals with energy intake of 2200 kcal day 2 1 (9.2 MJ day 2 1). addition, there has been a general increase in the use of lipids as formulation ingredients owing to their functional and biocompatible nature. As previously discussed, fatty acids of different chemical structure produce many different kinds of pharmacological effects. For instance, very long-chain o-3 PUFA may be used as a drug for its Intake of saturates ability to decrease plasma triacylglycerols, to decrease – milk- and meat-products, hard margarine blood coagulation and to reduce certain forms of Intake of trans fatty acids inflammations, in particular rheumatoid arthritis. – margarine with PHFO, milk products In addition to the therapeutic use of fatty acids, ω-3 fatty acids diagnostics based on lipids have been developed. More- – fatty fish, cod liver oil, fish oil over, fatty acids themselves or as part of complex lipids, are Vitamins D and E frequently used in cosmetics as soaps, fat emulsions, – fatty fish, cod liver/fish oil, grain, soya bean oil liposomes, etc. Figure 7 Advice for dietary lipids. Further Reading Fatty acids are widely used as excipients. The use of lipid formulations as the carrier for active substances is growing Caygill CP, Charlett A and Hill MJ (1996) Fat, fish, fish oil and cancer. rapidly, and we have probably only seen the beginning of British Journal of Cancer 74: 159–164. Drevon CA, Nenseter MS, Brude IR et al. (1995) Omega-3 fatty acids – lipids as active ingredients. The largest volume of lipids in nutritional aspects. Canadian Journal of Cardiology 11 (supplement pharmaceuticals are used in the production of fat emul- G): 47–54. sions, mainly for clinical nutrition, but also as drug Endres S, De Caterina R, Schmidt EB and Kristensen SD (1995) n-3 vehicles. Another lipid formulation is the liposome, which polyunsaturated fatty acids: update 1995. European Journal of Clinical is a lipid particle for incorporation of active ingredients. In Investigation 25: 629–638. 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
  7. 7. Fatty Acids: Structures and Properties Gurr MI and Harwood JL (1991) Fatty acid structure and metabolism. Rustan AC, Nenseter MS and Drevon CA (1997) Omega-3 and omega-6 In: Gurr MI and Harwood JL (eds) Lipid Biochemistry, An fatty acids in the insulin resistance syndrome: lipid and lipoprotein Introduction. London: Chapman and Hall. metabolism and atherosclerosis. Annals of the New York Academy of Harris WS (1997) n-3 fatty acids and serum lipoproteins. American Sciences 827: 310–326. Journal of Clinical Nutrition 65 (supplement 5): 1645–1654. Storlien L, Hulbert AJ and Else PL (1998) Polyunsaturated fatty acids, Nenseter MS and Drevon CA (1996) Dietary polyunsaturates and membrane function and metabolic diseases such as diabetes and peroxidation of low-density lipoproteins. Current Opinion in Lipidol- obesity. Current Opinion in Clinical Nutrition and Metabolic Care 1: ogy 7: 8–13. 559–563. ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 7

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