Fatty Acids

Fatty Acids: Structures andPropertiesArild C Rustan, University of Oslo, Oslo, Norway

Christian A Drevon, University of Oslo, Oslo, Norway

Fatty acids play a key role in metabolism: as a metabolic fuel, as a necessary component of

all membranes and as a gene regulator. In addition, fatty acids have a number of industrial

uses.

Introduction

Fatty acids, both free and as part of complex lipids, play anumber of key roles in metabolism – as a major metabolicfuel (storage and transport of energy), as essentialcomponents of all membranes and as gene regulators(Table 1). In addition, dietary lipids provide polyunsatu-rated fatty acids (PUFAs) that are precursors of powerfullocally acting metabolites, i.e. the eicosanoids. As part ofcomplex lipids, fatty acids are also important for thermaland electrical insulation, and for mechanical protection.Moreover, free fatty acids and their salts may function asdetergents and soaps owing to their amphiphatic proper-ties and formation of micelles.

Overview of Fatty Acid Structure

Fatty acids are carbon chains with a methyl group at oneend of the molecule (represented by omega, o) and acarboxyl group at the other end (Figure1). The carbonatomnext to the carboxyl group is called the a carbon. The lettern is also often used instead of the Greek o to represent themethyl end. The systematic nomenclature for fatty acidswhere the locations of double bonds are indicated withreference to the carboxyl group (D) is also commonly used.Figure 2 outlines the structures of different types ofnaturally occurring fatty acids.

Saturated fatty acids

Saturated fatty acids are ‘filled’ (saturated) with hydrogen.Most saturated fatty acids are straight hydrocarbon chainswith an even number of carbon atoms. The most commonfatty acids contain 12–22 carbon atoms.

Unsaturated fatty acids

Monounsaturated fatty acids have one double bond thatcan occur in different positions. The most commonmonoenes have a chain length of 16–22 and a doublebond with the cis configuration. This means that thehydrogen atoms on either side of the double bond areoriented in the same direction. Often the cis bond is foundat D9–10. Trans isomers may be produced duringindustrial processing (hydrogenation) of unsaturated oilsand in the gastrointestinal tract of ruminants. The presenceof a double bond causes restriction in themotionof the acylchain at that point. The cis configuration gives a kink in themolecular shape and cis fatty acids are thermodynamicallyless stable than the trans forms. The cis fatty acids havelower melting point than the trans fatty acids or theirsaturated counterparts.In polyunsaturated fatty acids (PUFAs) the first double

bond may be found between the third and the fourthcarbon atom from the o carbon; these are called o-3 fattyacids. If the first double bond is between the sixth andseventh carbon atom, then they are called o-6 fatty acids.The double bonds in PUFAs are separated from each otherby a methylene group.PUFAs, which are produced only by plants and

phytoplankton, are essential to all higher organisms,

Article Contents

Introductory article

. Introduction

. Overview of Fatty Acid Structure

. Major Fatty Acids

. Properties of Fatty Acids

. Requirements/Uses of Fatty Acids in Human Nutrition

. Uses of Fatty Acids in the Pharmaceutical/Personal

Hygiene Industries

Table 1 Functions of fatty acids

Energy – high, low weight/energy unitTransport form of energy – blood lipids (triacylglycerol inlipoproteins)

Storage of energy – adipose tissue (obesity)Component of cell membranes (phospholipids)Isolation – thermal, electrical and mechanicalSignals – eicosanoids, gene regulation (transcription)

CH – (CH ) – CH – CH – COOH3 2 nω β α

2 2

Figure 1 Nomenclature for fatty acids. Fatty acids may be namedaccording to systematic or trivial nomenclature. One systematic way todescribe fatty acids is related to the methyl (o) end. This is used to describethe position of double bonds from the end of the fatty acid. The letter n isalso often used to describe the o position of double bonds.

1ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

including mammals. o-3 and o-6 fatty acids cannot beinterconverted, and both are essential nutrients. PUFAsare further metabolized in the body by addition of carbonatoms and desaturation (extraction of hydrogen). Mam-mals have desaturases that are capable of removinghydrogens only from carbon atoms between an existingdouble bond and the carboxyl group (Figure 3). bOxidationof fatty acids may take place in either mitochondria orperoxisomes.

Major Fatty Acids

The most common saturated fatty acid in animals, plantsand microorganisms is palmitic acid (16:0). Stearic acid(18:0) is amajor fatty acid in animals and some fungi, and aminor component inmost plants.Myristic acid (14:0) has awidespread occurrence, occasionally as a major compo-nent. Shorter-chain saturated acids with 8–10 carbonatoms 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 inmicroorganisms. Palmitoleic acid (16:1, o-7) also occurswidely in animals, plants and microorganisms, and is amajor component in some seed oils.Linoleic acid (18:2, o-6) is a major fatty acid in plant

lipids. In animals it is derived only from dietary vegetables,plants and marine oils. Arachidonic acid (20:4, o-6) is amajor component of animal phospholipids. It is also amajor component of marine algae and some terrestrialspecies, but very little is found in the diet. a-Linolenic acid(18:3, o-3) is found in higher plants and algae. Eicosa-pentaenoic acid (EPA; 20:5, o-3) and docosahexaenoicacid (DHA; 22:6, o-3) are major fatty acids of marinealgae, fish and fish oils. These fatty acids are found inanimals, especially in phospholipids in the brain, retinaand testes.

Properties of Fatty Acids

Physical properties

The short-chain fatty acids with chain lengths up to eightcarbon atoms are poorly water-soluble, but they arepresent in low concentrations. The actual solubility,

Linoleic 18:2 α-Linolenic 18:3

∆ 6-desaturase

γ-Linolenic 18:3 Octadecatetraenoic 18:4elongase

Dihomo-γ-linolenic 20:3 Eicosatetraenoic 20:4

∆ 5-desaturase

Arachidonic 20:4 Eicosapentaenoic 20:5

elongase

Adrenic 22:4 Docosapentaenoic 22:5

elongase

Tetracosatetraenoic 24:4 Tetracosapentaenoic 24:5

∆ 6-desaturase

Tetracosapentaenoic 24:5 Tetracosahexaenoic 24:6

β-oxidation

Docosapentaenoic 22:5 Docosahexaenoic 22:6

ω-3 Fatty acidsω-6 Fatty acids Enzymes

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 thebody as shown in this figure. Retroconversion, e.g. DHA!EPA also takesplace.

ω-characteristic Methyl end Carboxyl end Saturation ∆-characteristics

Stearic acid 18:0

Oleic acid 18:1, ω-9

Linoleic 18:2, ω-6

α-Linolenic 18:3, ω-3

DHA 22:6, ω-3

6 12 9

3

EPA 20:5, ω-3

19 16 13 10 7 4

3 17 14 11 8 5

COOH 18:0

COOH 18:1 ∆ 9

COOH 18:2 ∆ 9,12

COOH 18:3 ∆ 9,12,15

COOH 22:6 ∆ 4,7,10,13,16,19

COOH 20:5 ∆ 5, 8,11,14,17

15 12 9

3

9 9Saturate

Monoene

Polyene

Polyene

Polyene

Polyene

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 18carbon 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 thefatty 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.

Fatty Acids: Structures and Properties

2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

particularly of longer-chain acids, is often very difficult todetermine since it is markedly influenced by pH, and alsobecause fatty acids have a tendency to associate, leading tothe formation of monolayers or micelles. Formation ofmicelles in aqueous solutions of lipids is associated withvery rapid changes in physical properties over a limitedrange of concentration. The point of change is known asthe critical micellar concentration (CMC), and exemplifiesthe tendency of lipids to self-associate rather than remainas single molecules. The CMC is not a fixed value, but is asmall concentration range that is markedly affected by thepresence of other ions, neutral molecules, etc.Fatty acids are easily extracted with non-polar solvents

from solutions or suspensions by lowering the pH to formthe uncharged carboxyl group. In contrast, raising the pHincreases solubility because of the formationof alkalimetalsalts, which are familiar as soaps. Soaps have importantproperties as association colloids and are surface-activeagents.The influence of fatty acid structure on its melting point

is that branched chains and cis double bonds will lower themelting point compared with equivalent saturated chains.In addition, the melting point of a fatty acid depends onwhether the chain is even- or odd-numbered; the latterincreases the melting point.Saturated fatty acids are very stable, whereas unsatu-

rated acids are susceptible to oxidation: the more doublebonds, the greater the susceptibility. Unsaturated fattyacids, therefore, shouldbehandledunder an atmosphere ofinert gas and kept away from oxidants and compoundsthat give rise to free radicals. Antioxidants may be veryimportant in the prevention of potentially harmful attackson acyl chains in vivo (see later).For most chemical reactions, fatty acids have to be

‘activated’ by forming thiol esters. The active form of fattyacids is usually the thiol ester with the complex nucleotidecoenzyme A (CoA), which also makes the acyl chainswater-soluble. The acyl–CoA molecules can, for example,be used for oxidation and esterification.

Biological effects

The different mechanisms by which fatty acids caninfluence biological systems are outlined in Figure 4.

Eicosanoids

Eikosa means 20 in Greek, and denotes the number ofcarbon atoms in the polyunsaturated fatty acids that act asprecursors of eicosanoids (Figure 5). These signal mole-cules, which are formed in several different ways, are calledleucotrienes, prostaglandins, thromboxanes, prostacy-clins, lipoxins and hydroxy fatty acids. Eicosanoids areimportant for several cellular functions such as plateletaggregability (ability to clump and fuse), chemotaxis(movement of blood cells) and cell growth. Eicosanoids

are mostly formed in cells where they execute their effects,and they are rapidly formed and degraded. Different celltypes produce different types of eicosanoids with differentbiological functions. For example, platelets mostly makethromboxanes, whereas endothelial cells mainly produceprostacyclins. Eicosanoids from theo-3 PUFA are usuallyless potent than eicosanoids derived from the o-6 fattyacids (Figure 6).

Substrate specificity

The activities of fatty acids may be dependent on theirhaving a higher or lower ability to interact with enzymes orreceptors, as compared with other fatty acids. Forexample,EPA is a poorer substrate thanall other examinedfatty acids for esterification to cholesterol and diacylgly-cerol. Some o-3 fatty acids are preferred substrates forcertain desaturases. The preferential incorporation of o-3fatty acids into some phospholipids occurs because o-3fatty acids are preferred substrates for the enzymesresponsible for phospholipid synthesis. These examplesof altered substrate specificity of o-3 PUFA for certainenzymes illustrate why EPA andDHA aremostly found incertain phospholipids.

Membrane fluidity

When large amounts of very long-chain o-3 fatty acids areingested, there is a high incorporation of EPA andDHA inmembrane phospholipids. An increased amount of o-3PUFA may alter the physical characteristics of themembranes. Altered fluidity may lead to changes ofmembrane protein functions. The very large amount of

Eicosanoids

Transcription factors

Substrate specificity

Lipid peroxidation

Membrane flexibility

Acylation of proteins

ω-3

Platelets Whiteblood cell ω-3

Chemotacticagent

CH3 COOHCH3 COOH

Red blood cellsmore flexible cell

Protein Fatty acid

Membrane

Fatty acid

Promoter

Nucleus

DNAmRNA

Protein

Figure 4 Mechanisms of action for fatty acids. Thromboxanes formed inblood platelets promote aggregation (clumping) of blood platelets.Leucotrienes in white blood cells act as chemotactic agents (attractingother white blood cells). See Figure 6.



DHA in phosphatidylethanolamine and phosphatidylser-ine in certain areas of the retinal rod outer segments isprobably crucial for the function of membrane phospho-lipids in light transduction, since these lipids are locatedclose to the rhodopsin molecules. It has been shown thatthe flexibility ofmembranes fromblood cells in animals fedfish oil is markedly increased, and this might be importantfor the microcirculation. Increased incorporation of verylong-chain o-3 PUFA into plasma lipoproteins changesthe physical properties of low-density lipoproteins (LDL),lowering the melting point of core cholesteryl esters.

Lipid peroxidation

Lipid peroxidation products may act as biological signals.One of the major concerns with intake of PUFAs has beentheir high degree of unsaturation, and therefore thepossibility that they might promote the peroxidation of

low-density lipoproteins (LDL). Modified LDL might beendocytosed by macrophages and initiate development ofatherosclerosis. Oxidativelymodified LDLhas been foundin atherosclerotic lesions, and LDL rich in oleic acid wasfound to be more resistant to oxidative modification thanLDL enriched with o-6 fatty acids in rabbits. Althoughsome of the published data are conflicting, several of thewell-performed studies indicate small or no harmful effectsof o-3 fatty acids. From epidemiological studies it shouldbe recalled that the dietary intake of saturated fatty acids,trans fatty acids and cholesterol is strongly correlated todevelopment of coronary heart diseases, whereas intake ofPUFA is related to reduced incidence of coronary heartdiseases. Several studies suggest it is important that theproper amount of antioxidants is included in the diet withthe PUFA to decrease the risk of lipid peroxidation.

Acylation of proteins

Some proteins are acylated with stearic (18:0), palmitic(16:0) or myristic acid (14:0). This acylation of proteins isimportant for anchoring certain proteins in membranes orfolding of the proteins, and is crucial for the function ofthese proteins. Although the saturated fatty acids are mostcommonly covalently linked to proteins, PUFA may alsoacylate proteins.

Gene interactions

Fatty acids or their derivatives (acyl–CoA or eicosanoids)may interact with nuclear receptor proteins that bind tocertain regulatory regions of DNA and thereby altertranscription of these genes (Figure 4). The receptor proteinmay act in combination with a fatty acid functioning as atranscription factor. The first example of this was theperoxisome proliferator-activated receptor (PPAR). Nat-

5-Lipoxygenase 12-Lipoxygenase

Different enzymes

AA (EPA) in phospholipid / diacylglycerol

Arachidonic acid (EPA)

Cyclooxygenase (COX)

Leucotriene LTA (LTA )4 5 12-OH -acids

Cyclic endoperoxides

Prostaglandin Prostacyclin Thromboxane

LTC (LTC ) LTB (LTB )4 5 4 5

PGI (PGI )2 3 TXA (TXA )2 3

LTD (LTD )4 5

LTE (LTE )4 5 PGE (PGE )2 3

Figure 5 Synthesis of eicosanoids from arachidonic acid (AA) or eicosapentaenoic acid (EPA).

Fatty acid AA EPA AA EPA AA EPA

Enzyme Cyclooxygenase Lipoxygenase

Cell type

Eicosanoids

Platelets Endothelial cells Leucocytes

TXA2 TXA3 PGI2 PGI3 LTB4 LTB5

Aggregation +++ +Antiaggregation +++ +++Vasoconstriction +++Vasodilatation +++ +++

Biological effect

Chemotaxis +++ +

Figure 6 Biological effects of eicosanoids derived from arachidonic acid(AA; 20:4, o-6) or eicosapentaenoic acid (EPA; 20:5, o-3).



ural fatty acids are weak activators of PPAR, and this maybe explained by the rapid oxidation of fatty acids. If fattyacids are blocked from being b-oxidized, they are muchmore potent stimulators of PPAR than natural fatty acids.Fatty acids may also influence expression of severalglycolytic and lipogenic genes independent of PPAR. Ithas been demonstrated that one eicosanoid derived fromarachidonicacid,prostaglandinJ2(PGJ2),bindstoPPARg,which is an important transcription factor in adipose tissueand colon. Fatty acids as well as eicosanoids can binddirectly to PPARa and PPARg. PUFAmay also influenceproliferation of white blood cells, together with the cells,tendency to die by programmed cell death (apoptosis) ornecrosis. Thus, fatty acidsmay be important for regulationof gene transcription and thereby regulatemetabolism, cellproliferation and cell death.

Metabolic effects

Replacement of saturated fat with monounsaturated andpolyunsaturated fat (especially o-6 PUFA) decreases theplasma concentration of total and LDL cholesterol(Table 2). The mechanism for these effects is an increaseduptake of LDL particles from the circulation by the liver.Dietary very long-chain o-3 fatty acids (EPA and DHA)decrease plasma triacylglycerol levels by reducing produc-tion of triacylglycerol-rich lipoproteins. In addition toeffects on plasma lipids, dietary fatty acids can influencemetabolic and cardiovascular events in numerous ways, asshown in Table3. For instance, saturated fatmaynegativelyaffect several factors related to cardiovascular diseases andatherosclerosis, whereas very long-chain o-3 PUFAs havebeen shown to exert a number of beneficial effects upon thecardiovascular system. Briefly, o-3 PUFAs decreaseplatelet and leucocyte reactivity, inhibit lymphocyteproliferation, and may slightly decrease blood pressure.o-3 PUFAs may also beneficially influence vessel wallcharacteristics and blood rheology, prevent ventriculararrhythmias and improve insulin sensitivity. o-6 PUFAs

(mainly linoleic acid, 18:2, o-6) have also been shown tohave many beneficial effects with respect to cardiovasculardiseases (Table 3).

Requirements/Uses of Fatty Acids inHuman Nutrition

Although the data we have on the required intake ofessential fatty acids are relatively few, the adequate intakesof linoleic acid (18:2, o-6) and a-linolenic acid (18:3, o-3)should be 2%and1%of total energy, respectively (Table4).Present knowledge suggests that 0.2–0.3% of the energyshould be derived from preformed very long-chain o-3PUFAs (EPA and DHA) to avoid signs or symptoms ofdeficiency. This corresponds to approximately half a gramof these o-3 fatty acids per day. It should be stressed thatthis is the minimum intake to avoid clinical symptoms ofdeficiency. From many epidemiological and experimentalstudies there is relatively strong evidence that there aresignificant beneficial effects of additional intake of PUFAin general and very long-chain o-3 fatty acids (EPA andDHA) in particular. It is possible that the beneficial effectsmay be obtained at intakes as low as one to two fish mealsweekly, but many of the measurable effects on risk factorsare observed at intakes of 1–2 g day2 1 of very long-chaino-3 PUFA. If 1–2 g day2 1 of EPA and DHA is consumedin combination with proper amounts of fruits andvegetables, and limited amounts of saturated and transfatty acids, most people will probably benefit with betterhealth for a longer time (Figure 7).

Uses of Fatty Acids in thePharmaceutical/Personal HygieneIndustries

There are three different principles that justify the use offatty acids (or fatty acids as part of complex lipids) asingredients in pharmaceutical products. The formaldistinction between these three principles is explained bythe following definitions:

. excipients – these are physiologically inactive ingredi-ents in pharmaceuticals that enable delivery ofmedicinesin a variety of dosage forms;

. pharmaceutical formulation – a drug is an activecompound in a pharmaceutical formulation; and

. active ingredient – fatty acids may be used as activeingredients, i.e. as physiologically active drug sub-stances.

Table 2 Effect of fatty acids on plasma and LDL cholesterol

DCholesterol(mmol L2 1)

DLDL cholester-ol (mmol L2 1)

12:0 1 0.03 1 0.0314:0 1 0.12 1 0.1416:0 1 0.05 1 0.04TransMarin 1 0.035 1 0.04TransVeg 1 0.026 1 0.03718:1 2 0.003 2 0.00618:2/3 2 0.015 2 0.015

TransMarin, trans fatty acids of marine origin; transVeg, trans fattyacids of vegetable origin. Personal communication from Jan I.Pedersen, University of Oslo.



Fatty acids are widely used as excipients. The use of lipidformulations as the carrier for active substances is growingrapidly, and we have probably only seen the beginning oflipids as active ingredients. The largest volume of lipids inpharmaceuticals are used in the production of fat emul-sions, mainly for clinical nutrition, but also as drugvehicles. Another lipid formulation is the liposome, whichis a lipid particle for incorporation of active ingredients. In

addition, there has been a general increase in the use oflipids as formulation ingredients owing to their functionaland biocompatible nature. As previously discussed, fattyacids of different chemical structure produce manydifferent kinds of pharmacological effects. For instance,very long-chain o-3 PUFA may be used as a drug for itsability to decrease plasma triacylglycerols, to decreaseblood coagulation and to reduce certain forms ofinflammations, in particular rheumatoid arthritis.In addition to the therapeutic use of fatty acids,

diagnostics based on lipids have been developed. More-over, fatty acids themselves or as part of complex lipids, arefrequently used in cosmetics as soaps, fat emulsions,liposomes, etc.

Further Reading

Caygill CP, Charlett A and Hill MJ (1996) Fat, fish, fish oil and cancer.

British Journal of Cancer 74: 159–164.

Drevon CA, Nenseter MS, Brude IR et al. (1995) Omega-3 fatty acids –

nutritional aspects. Canadian Journal of Cardiology 11 (supplement

G): 47–54.

Endres S, De Caterina R, Schmidt EB and Kristensen SD (1995) n-3

polyunsaturated fatty acids: update 1995.European Journal of Clinical

Investigation 25: 629–638.

Table 3 Dietary fatty acids may influence metabolic and cardiovascular events

Event Negative influence Positive influence

Coronary artery disease Saturated o-3 PUFA and monoenesStroke Saturated ?Blood pressure Saturated o-3 PUFAInsulin resistance Saturated o-3 PUFABlood 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 monoenesOxidation of LDL o-6 PUFA (?) MonoenesAtherogenesis (leucocyte reactivity,immunological functions)

Saturated and monoenes (?) o-3 PUFA and o-6 PUFA

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).

Intake of saturates– milk- and meat-products, hard margarine

Intake of trans fatty acids– margarine with PHFO, milk products

ω-3 fatty acids– fatty fish, cod liver oil, fish oil

Vitamins D and E– fatty fish, cod liver/fish oil, grain, soya bean oil

Figure 7 Advice for dietary lipids.

Table 4 Suggested intake of essential PUFA

Intake o-3 (% of energy) o-6 (% of energy) o-3 (mg day2 1) o-6 (mg day2 1)

Minimum 0.2–0.3 1–3 400–600 2400–7200Optimum 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 ofrequired and optimal intake in healthy, normal individuals with energy intake of 2200 kcal day2 1 (9.2MJday2 1).



Gurr MI and Harwood JL (1991) Fatty acid structure and metabolism.

In: Gurr MI and Harwood JL (eds) Lipid Biochemistry, An

Introduction. London: Chapman and Hall.

Harris WS (1997) n-3 fatty acids and serum lipoproteins. American

Journal of Clinical Nutrition 65 (supplement 5): 1645–1654.

Nenseter MS and Drevon CA (1996) Dietary polyunsaturates and

peroxidation of low-density lipoproteins. Current Opinion in Lipidol-

ogy 7: 8–13.

RustanAC,NenseterMS andDrevonCA (1997) Omega-3 and omega-6

fatty acids in the insulin resistance syndrome: lipid and lipoprotein

metabolism and atherosclerosis. Annals of the New York Academy of

Sciences 827: 310–326.

Storlien L, Hulbert AJ and Else PL (1998) Polyunsaturated fatty acids,

membrane function and metabolic diseases such as diabetes and

obesity. Current Opinion in Clinical Nutrition and Metabolic Care 1:

559–563.



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