Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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certain tropical oils such as coconut and palm kernel

oils. Arachidic acid occurs, albeit in small amounts, in

a wide range of tropical vegetable fats. Animal fats, in

addition to palmitic and stearic acids, contain small

amounts of odd-numbered and branched-chain satur-

ated acids. The lower fatty acids from butyric (4:0)

to capric (10:0) are significant in ruminant milk fats.

(See Palm Oil.)

0007 The next four items in Table 1 are monounsatu-

rated fatty acids. Oleic acid is universally important

in food lipids, in some cases being as much as 80% of

the component fatty acids (e.g., olive oil). Palmitoleic

acid is also ubiquitous, though in much smaller

amounts. Erucic and petroselinic acids, though im-

portant in a few seed oils, are of restricted occurrence,

the former in the Cruciferae and the latter in the

Umbelliferae. Except for erucic acid, these and all

the acids referred to later in this section are liquid at

ambient temperatures.

0008 Linoleic acid is of almost universal importance in

vegetable oils, but it does not occur to a significant

extent in animal products. This diunsaturated fatty

acid, the only really important one, is the ‘essential

fatty acid’ on which most nutritional studies have

been based and is the key member of the widely

advertised ‘polyunsaturates.’

0009 The triunsaturated fatty acids, a- and g-linolenic

acids, are found, though very rarely together, in

many seed oils, the former being the commoner. a-

Linolenic acid is the major fatty acid of leaf and root

lipids and many seed oils, especially those of northern

latitudes. g-Linolenic acid, though less widespread, is

found in the oil seeds of many plant species, in some

algae and fungi and certain animal products.

0010 Of the last three fatty acids named in Table 1,

arachidonic acid is of exclusively animal origin

(e.g., eggs and certain meat offals) whilst the last

two occur in substantial proportions in fatty fish

(herring, mackerel) and fish liver oils (cod, halibut).

(See Fish Oils: Dietary Importance; Offal: Types of

Offal.)

0011Apart from those listed, and certain isomers and

homologs of them, many other fatty acids, though

less common, are well known. These may contain con-

jugated unsaturated systems (e.g., punicic acid), trans

double bonds (e.g., columbinic acid), triple bonds

(e.g., crepenynic acid), homocyclic (e.g., sterculic

acid) or heterocyclic (e.g., vernolic acid) rings or sub-

stituent functional groups (e.g., ricinoleic acid). Some

of these are occasionally consumed in food lipids.

Glycerides

0012Food scientists and technologists are much more con-

cerned with glycerides than with fatty acids as such.

Many, but not all, of the properties of fatty acids are

mirrored in those of the nonpolar triglycerides. How-

ever, the mono- and diglycerides, in which, respect-

ively, only one or two of the hydroxyls of glycerol are

esterified, have both lipophilic and hydrophilic prop-

erties. The resulting surface activity enables them to

serve as emulsifiers and foam stabilizers in processed

foods. (See Emulsifiers: Organic Emulsifiers; Uses in

Processed Foods.)

Mono- and Diglycerides

0013Monoglycerides containing a fatty acid (RCO

exist in the form of 1-monoglycerides (1) or the iso-

meric 2-monoglycerides (2). Both forms revert, on

storage, to an equilibrium mixture in which the

1-monoglyceride dominates (90%). Monoglycerides,

accompanied by diglycerides, are produced by the

base-catalyzed interesterification (randomization) of

a triglyceride (5) with glycerol. The resulting mixed

product is often used without purification, but if

high-quality monoglycerides are desired, these can

be obtained by molecular distillation of the mixed

product. Monoglycerides have important applica-

tions in the food-processing industry for the sta-

bilization of both water-in-oil (e.g., margarine) and

oil-in-water (e.g., artificial cream) emulsions. (See

Margarine: Methods of Manufacture.)

(1)

RCO

(2)

RCO

(3)

RCO

(4)

RCO

(5)

RCO

0014Diglycerides also exist in two forms ((3) and (4)),

the 1,3-diglyceride (3) being dominant in the

tbl0001 Table 1 The more important natural food fatty acids

Trivialname Empirical formula Shorthand structure

Lauric acid C

H 12:0

Myristic acid C

H 14:0

Palmitic acid C

H 16:0

Stearic acid C

H 18:0

Arachidic acid C

H 20:0

Palmitoleic acid C

H 16:1 n-7

Oleic acid C

H 18:1 n-9

Petroselinic acid C

H 18:1 n-12

Erucic acid C

H 22:1 n-9

Linoleic acid C

H 18:2 n-6

a-Linolenic acid C

H 18:3 n-3

g-Linolenic acid C

H 18:3 n-6

Arachidonic acid C

H 20:4 n-6

Eicosapentaenoic acid

H 20:5 n-3

Docosahexaenoic acid

H 22:6 n-3

In these cases, systematic names are given in the absence of trivial

names.

2298 FATTY ACIDS/Properties

equilibrium mixture. They are much less polar than

monoglycerides and have few food applications.

Triglycerides

0015 These are the dominant components (more than

90%) of all edible oils and fats. Since they contain

about four to 10 significant amounts of different fatty

acids, they comprise a very large number of individual

triglycerides. The fatty acids are, however, not ran-

domly distributed but tend to follow certain rules.

0016 In oils and fats of vegetable origin, the preferred

sites for saturated acids are the 1- and 3-positions,

whilst unsaturated acids occupy the 2-position for

preference. In animal fats (e.g., lard), the reverse is

the case, except for the fats of ruminants (e.g., beef

and mutton tallow, milk fat), in which the distribu-

tion is approximately random.

0017 The positions of substituent saturated and unsatur-

ated fatty acids in the triglyceride molecule are im-

portant in determining the hardness, elasticity, and

melting characteristics (Table 2) of fats containing

them. These physical parameters control the texture

and mouth-feel of foods in which they are major

components. Such compositional features are parti-

cularly important in the case of monounsaturated

disaturated triglycerides, which can be represented

as the isomers SUS and SSU.

0018 Relatively hard vegetable fats (SUS-type triglycer-

ides, 30–40



C), such as cocoa butter melt sharply at,

or slightly below, body temperature and hence are ideal

components in chocolate, cream fillings, and confec-

tionery couvertures. Admixture with fats of the

SSU-type causes a fall in melting point and a marked

increase in melting range. Such mixed triglycerides

may therefore be well adapted to the formulation of

margarines and bakery fats. (See Cocoa: Production,

Products, and Use; Fats: Uses in the Food Industry.)

0019 The melting and crystallization characteristics of

both pure and mixed triglycerides are also very de-

pendent on ‘tempering’ (close control of holding time

and temperature), since they exist in distinct poly-

morphic forms, the most stable being that with the

highest melting point.

0020Natural fats can be physically separated into desir-

able fractions by various industrial processes, viz. by

‘dry,’‘wet,’ or ‘solvent’ fractionation, with appropri-

ate careful temperature control. Fats such as edible

tallow, lard, palm oil, palm kernel oil, and coconut oil

can, in the ‘dry’ process, be separated by pressing or

filtration into a higher-melting crystalline fraction

and a liquid oil. In the ‘wet’ processes, the fat is

mixed with an aqueous solution of a surface-active

agent, which disperses the crystalline fraction into the

aqueous phase. The separation is more efficient than

in the dry processes. The most efficient and selective

fractionation process makes use of a volatile solvent,

usually acetone, to segregate, to a large extent, glycer-

ides according to their degree of unsaturation: SSS,

SUS, SUU, and UUU.

Reactions of Triglycerides

0021In the context of food, very few intentional reactions

are permissible, since both the starting material and

the reaction product must be of acceptable edible

quality. Thus, only two kinds of reactions are of

practical importance – hydrogenation and interester-

ification. To these, however, must be added lipolysis

and autoxidation – undesirable spoilage reactions

affecting oils and fats under unfavorable storage con-

ditions, and thus causing rancidity.

0022Hydrogenation The objects of hydrogenation are

(1) by increasing the degree of saturation of an oil

or fat to raise its melting point and thus extend its

applications, and (2) by reducing its degree of unsat-

uration to reduce its proneness to autoxidation and

thereby to enhance its stability. Hydrogenation is

always partial and sometimes only marginal. In

chemical terms, it involves not only the saturation of

double bonds but also cis–trans isomerization and

migration of some double bonds to neighboring

positions in the fatty chains.

0023Hydrogenation involves the use of hydrogen and a

supported metal catalyst, commonly nickel on Kiesel-

guhr, at temperatures between 100 and 200



C. Con-

ditions are varied according to requirements. Thus,

the use of a fresh catalyst and low temperatures min-

imizes isomerization, whereas an old (‘poisoned’)

catalyst at higher temperatures promotes isomeriza-

tion and minimizes saturation. Trans fatty acids can

be formed in high proportions in hydrogenated fats,

with consequent rises in melting points (note the con-

trast in melting points between corresponding cis and

trans 18:1 n-9 compounds in Table 2).

0024Interesterification The same base-catalyzed reac-

tion, as described earlier for the production of mono-

glycerides, is applicable to the randomization of

tbl0002 Table 2 Melting points (



C) of fatty acids and derived

glycerides

Fattyacid 1-Monoglyceride 1,3-Diglyceride Triglyceride

12:0 44 63 56 46

14:0 54 70 65 57

16:0 63 77 72 65

18:0 70 81 78 73

18:1 n-9 (cis)1635 21 5

18:1 n-9 (trans)4458 55 42

18:2 n-6 612 3 13

FATTY ACIDS/Properties 2299

individual fats or to the randomization of mixtures of

two or more fats or oils. The process has several

advantages. For example, lard, which in its natural

form solidifies very slowly on cooling, producing

large, ‘grainy’ crystals, after interesterification, rap-

idly sets on cooling to a compact mass of very small

crystals. Edible tallow, with an inconveniently high

melting point, after interesterification with a soft oil,

such as soya bean oil, yields a soft fat with a very

usefulmeltingrange.(SeeSoy(Soya)Beans:TheCrop.)

0025 Lipolysis Triglycerides are hydrolyzed, albeit very

slowly, by aqueous media, but much more rapidly

by basic catalysts and, more importantly, by endogen-

ous lipolytic enzymes. Oils and fats (e.g., olive oil,

palm oil, tallow) from fruit coats or animal tissues

are particularly prone to lipolysis if they are allowed

to remain too long in contact with bruised tissue

before processing. As a result of such handling,

major processing losses are suffered as a result of the

need to carry out refining operations to remove harsh

flavor taints.

0026 Autoxidation Access of atmospheric oxygen to

unsaturated fatty acids or glycerides leads to deterior-

ation through oxidation. Saturated and monounsatu-

rated fatty chains oxidize very slowly and do not as a

rule cause problems. Diunsaturated chains, as in 18:2

n-6, oxidize more rapidly and polyunsaturated chains

very rapidly. Oils such as fish oils are so liable to

oxidative degradation that they cannot be used as

such in food formulation but must first be hydrogen-

ated. (See Oxidation of Food Components.)

0027 Autoxidation depends on free-radical chain reac-

tions, which involve the interaction of oxygen with

free radicals generated at methylene groups adjacent

to double bonds, especially at methylene groups be-

tween two double bonds. Hydroperoxides are thus

formed, and these, being unstable, break down to

fission products, including some of low molecular

weight. Equation (1) is a summary of a typical reac-

tion sequence.

and R

are alkyl and alkylene portions of the fatty

chain; G is the nonvolatile glyceride residue.)

0028The aldehydes and other volatile oxidation prod-

ucts have strong, unattractive odors and flavors, and

make a predominating contribution to ‘rancidity.’

Further, peroxides are toxic food components, so

autoxidation must be minimized by all possible

means. It can be avoided, or at least greatly delayed,

by careful and prompt handling and storage of oils

and fats, by avoidance of prooxidative situations such

as contact with metals, and by the use of various

kinds of antioxidants that inhibit steps in the autoxi-

dation process. (See Antioxidants: Natural Antioxi-

dants; Synthetic Antioxidants.)

See also: Antioxidants: Natural Antioxidants; Synthetic

Antioxidants; Cocoa: Production, Products, and Use;

Emulsifiers: Organic Emulsifiers; Uses in Processed

Foods; Fats: Classification; Uses in the Food Industry;

Fish Oils: Dietary Importance; Margarine: Methods of

Manufacture; Offal: Types of Offal; Oxidation of Food

Components; Palm Oil; Phospholipids: Properties and

Occurrence; Soy (Soya) Beans: The Crop;

Triglycerides: Structures and Properties

Further Reading

Allen JC and Hamilton RJ (1989) Rancidity in Foods.

London: Elsevier Applied Science.

Chapman D (1965) The Structure of Lipids by Spectro-

scopic and X-ray Techniques. London: Methuen.

Forss DA (1972) Odour and flavour compounds from

lipids. In: Holman RT (ed.) Progress in the Chemistry

of Fats and Other Lipids, vol. 13. Oxford: Pergamon

Press.

Gunstone FD (1967) An Introduction to the Chemistry

and Biochemistry of Fatty Acids and their Glycerides.

London: Chapman & Hall.

Gurr MI and James AT (1975) Lipid Biochemistry: an

Introduction. London: Chapman & Hall.

Hilditch TP and Williams PN (1964) The Chemical Consti-

tution of Natural Fats. London: Chapman & Hall.

Hudson BJF (ed.) (1990) Food Antioxidants. London:

Elsevier Applied Science.

Markley KS (ed.) (1967) Fatty Acids, their Chemistry,

Properties, Production and Uses. New York: Inter-

science.

Mostofsky DI, Yehuda S and Salem N (eds) (2001) Fatty

Acids: Physiological and Behavioral Functions. Totowa,

USA: Humana Press.

Patterson HBW (1983) Hydrogenation of Fats and Oils.

London: Elsevier Applied Science.

Patterson HBW (1989) Handling and Storage of Oilseeds,

Oils, Fats and Meal. London: Elsevier Applied Science.

Swern D (ed.) (1979) Baily’s Industrial Oil and Fat Prod-

ucts, 4th edn. New York: Wiley.

−CH

CH−CH

−R

−GR

−CH

CH−CH−R

−G

−CH

−

CHO + HO−R

−G

OOH

(1)

2300 FATTY ACIDS/Properties

Metabolism

P Mun

iz, Universidad de Burgos, Burgos, Spain

Fatty Acid Availability

0001 Fatty acids are the principal form of stored energy for

most organisms. Almost all tissues can utilize fatty

acids for energy, exceptions being the brain, blood

cells, skin, and renal medulla. The fatty acids present

two advantages compared with other energetic

biomolecules: their high energy density and low

solubility. Thus, oxidation of tryacylglycerols releases

37 kJ g

1

compared with the 16–17 kJ g

1

for sugars,

glycogen, and amino acids, and fatty acids can be

stored without water.

0002 Most of these fatty acids are stored in adipose

tissue, comprising specialized cells, the adipocytes.

Mammals can store 5–25% or more of their body

weight in the form of lipids, and 90% of these lipids

are tryacylglycerols (TGs). The fat storage is not

static, so the tryacylglycerols are in a constant state

of turnover. The liver, the major center of lipid

metabolism, is largely responsible for regulating

lipid levels in the body. Among its important func-

tions are: synthesis of TG from fatty acids, synthesis

of other lipids such as phospholipids and cholesterol,

desaturation of fatty acids, and catabolism of tryacyl-

glycerols for use as energy.

0003 Since most of the tissues contain only small

amounts of storage lipids, energy production depends

on a continuous supply of fatty acids. The fatty acids

are derived primarily from two sources: exogenous

TG obtained from diet and endogenous TG stores

mainly in the adipose tissue.

Diet Fatty Acids

0004 Tryacylglycerols are the predominant type of lipid

ingested by humans, and they are absorbed as fatty

acids from the intestinal mucosa (enterocytes) into

the lymphatic system. The free fatty acids (FFAs)

inside the enterocytes are reesterified into TGs and

packaged with proteins and phospholipids to form

chylomicrons. Chylomicrons enter the lymphatic

system and eventually into the circulatory system at

the thoracic duct.

0005 Most of the chylomicrons are removed from the

blood into cells by the action of lipoprotein lipase, an

enzyme located on endothelial cell lining the capillar-

ies primarily in adipose tissue, skeletal and cardiac

muscle, and the liver. Lipoprotein lipase hydrolyzes

the TGs into fatty acids and glycerol, and is taken up

into these specific tissues. In adipose tissue, the FFAs

are primarily reesterified and stored as TGs, in other

organs as muscle and liver, and small amounts of TG

are stored intracellularly. The primary sites of FFA

oxidation are cardiac and skeletal muscle and liver.

Adipose Tissue Fatty Acids: Lipolysis

0006Fat stored as tryacylglycerols in adipose tissue and

mobilized in the form of plasma free fatty acids is

the main source of energy in the absence of dietary

substrates; up to 150 g of fatty acids can be liberated

daily, corresponding approximately to half of the

daily caloric needs.

0007Hydrolysis of adipose tissue TGs occurs via three

consecutive reactions and is catalyzed by two

enzymes: the triacylglicerol lipase, also called hor-

mone-sensitive lipase (HSL), and the monoglyceride

lipase (MGL). The rate-limiting enzyme in adipose

tissue lipolysis is HSL. HSL hydrolyzes TGs and

diglycerides, whereas the participation of MGL is

required for complete hydrolysis of monoglycerides.

Then, the three FFA molecules leave the adipose cell

and enter the circulation, where they are transported

bound to albumin. The remaining glycerol backbone

also leaves the cell, because adipose tissue does not

contain the enzyme glycerol kinase, and so glycerol is

not reutilized for reesterification in adipocytes.

0008HSL exhibits a preference, although not absolute,

for the (n-3/n-6) fatty acids from TGs, with approxi-

mately three- to fourfold higher hydrolysis rates to

the 1(3)-ester bonds than to the 2-ester bond. Fatty

acids, i.e., oleic and oleoyl coenzyme A (CoA), and

monoacyglycerols have been shown as inhibitors to

HSL. This feedback inhibition was proposed to pre-

vent the accumulation of fatty acids and free choles-

terol in the cells and to ensure that the capacity of

MGL to hydrolyze MGs is not exceeded. Recently,

adipocyte lipid-binding protein (ALBP) was shown to

interact with HSL, raising the possibility that ALBP

sequesters fatty acids resulting from HSL-catalyzed

lipolysis, and thus preventing the feedback inhibition

by lipolytic products.

0009Regulation of adipocyte lipolysis Fatty acid concen-

trations are the result of the balance between the rate

of appearance (lipolysis) and the rate of clearance.

Today, it is generally accepted that lipolysis is con-

trolled mainly by the activity of the sympatic nervous

system and by plasma insulin levels. The main regula-

tor factor of the rate of adipose tissue lipolysis is the

activity of HSL.

0010HSL activity is mainly regulated by the circulating

concentrations of insulin and epinephrine. These

hormones can change during times of stress, such as

FATTY ACIDS/Metabolism 2301

starvation, trauma, or physical exercise, or after feed-

ing, resulting in an alteration in lipolytic rates and

FFA concentrations. Insulin decreases the activity of

hormone-sensitive lipase, which is responsible for the

breakdown of adipose TG and concomitant release of

the free fatty acids into the circulation. Epinephrine,

norepinephrine, and adrenocorticoids, especially ad-

renocorticotropic hormone, increase the rate of fat

mobilization by stimulating HSL activity.

0011 HSL is hormonally regulated via phosphorylation/

dephosphorylation. The hormone stimulated by

HSL acts through a membrane-bound receptor and

activates the membrane-bound enzyme adenylate

cyclase, resulting in an increase in cyclic adenosine

monophosphate (cAMP) levels in the adipocyte.

cAMP directly activates a protein kinase A (PKA),

which phosphorylates and activates HSL. Lipolytic

agents generally increase the levels of cAMP far

above the concentrations required for maximal

activation of protein kinase A.

0012 Epinephrine is the primary stimulator of lipolysis

working through a b-adrenergic receptor in the

plasma membrane of the adipose cell resulting in

phosphorylation and activation of HSL. The physio-

logical state can affect the sensitivity to epinephrine.

For example, in short-term (3-day) fasting, the

lipolytic responsiveness to epinephrine infusion is

enhanced, whereas in obesity, the responsiveness to

epinephrine is blunted. Catecholamines are able to

stimulate lipolysis via three subtypes of b-adrenergic

receptors, which are positively coupled to adenyl

cyclase by Gs proteins and to inhibit lipolysis via

a2-adrenergic receptors, negatively coupled to the

enzyme by Gi proteins. In humans, the interplay

between a2 and b-adrenergic receptors plays an

important role in modulating cAMP levels in

adipocytes.

0013 However, the inhibition of HSL catalyzes its

dephosphorylation, and so insulin induces a decrease

in cAMP levels and a concomitant decrease in

PKA activity, and inhibits HSL, thus catalyzing its

dephosphorylation. Glucose is the predominant

signal for insulin release, so an effect of glucose intake

on lipolysis would be expected. Thus, in humans, an

increase in glucose concentration in the plasma stimu-

lates insulin release with concomitant increase in glu-

cose uptake and fatty acid reesterification, and a

decrease in lipolysis. The inhibitory effect of glucose

on lipolysis is mediated entirely by insulin.

0014 Under most physiological circumstances, the rate

of lipolysis is largely determined by the balance

between the stimulatory effect of epinephrine and

the inhibitory effect of insulin. For example, in

short-term fasting, there is a marked increase in

the rate of lipolysis, which can be attributed to

both a decrease in blood glucose (and thus insulin)

concentration and an increase in epinephrine concen-

tration and sensitivity to epinephrine. The striking

aspect of the regulation of lipolysis is that the factors

that are primary regulators (insulin and epinephrine)

are not released in response to a signal related to any

aspect of fatty acid metabolism. For example, acute

changes in fatty acid concentrations by infusion do

not affect insulin, catecholamines, or the rate of lipo-

lysis. Therefore, insulin and catecholamines, rather

than being primary regulators of lipolysis, may be

considered to be regulators of other physiological

and metabolic processes that also affect lipolysis. In

fact, the rate of resting lipolysis generally provides

fatty acids at a rate that is far in excess of the rate

required for oxidation. Fatty acids that are released

from adipocytes, but not oxidized, are reesterified,

thereby completing a substrate cycle.

Cellular Uptake of Fatty Acid

0015Fatty acids from the diet or produced by lipolysis are

transported, bound to proteins in blood, and their

cellular uptake is similar. The majority of complex

lipid is hydrolyzed by two related lipases, hepatic

lipase and lipoprotein lipase, and this hydrolysis

enables free fatty acids to enter cells.

0016The uptake of fatty acids across the plasma mem-

brane takes place either by diffusive processes, involv-

ing partitioning of the fatty acid molecule into

the lipid bilayer of the plasma membrane, or by the

presence of different lipid-binding proteins in the cell

membranes, called plasma membrane fatty-acid-

binding proteins (FABPpms).

0017At least five plasma membrane-associated fatty

acid binding proteins were proposed to play a role

in free fatty acid (FFA) uptake, a plasma membrane

fatty-acid-binding protein (FABPpm, 40 kDa), fatty

acid translocase (FAT, 88 kDa), fatty acid transport

protein (FATP 63 kDa), caveolin, and 56-kDa kidney

fatty acid binding protein. Once inside the cell, fatty

acids are bound noncovalently to a family of intra-

cellular fatty acid-binding proteins (FABPs) that may

play a role in the transfer of FFAs to intracellular

destinations where they are used. FABPs comprise a

family of 14–15-kDa proteins that bind long-chain

fatty acids.

Catabolism of Fatty Acids

0018Once within the cell and depending on the tissue and

its metabolic demand, fatty acids are either converted

to tryacylglycerols or membrane phospholipids, or

oxidized in the mitochondria for energy production.

Some metabolic routes are common to most of the

2302 FATTY ACIDS/Metabolism

cells, like b-oxidation, whereas others are tissue-

specific for prostanoid synthesis.

001 9 Before being directed into storage or membranes or

oxidation, fatty acids are first activated to acyl-CoAs.

Fatty Acids Activation and Transport into

Mitochondria

0020 A requisite step for fatty acid entering several meta-

bolic pathways is the formation of fatty acyl-CoA-

thioesters, catalyzed by fatty acyl-CoA synthetase,

with some substypes showing fatty acid chain-length

specificity. The fatty acyl-CoA products of these

enzymes are also bound to FABP.

002 1 Short- and medium-chain fatty acids are trans-

ported into the mitochondria matrix as free acids

and form the acyl-CoA derivatives over there. How-

ever, long-chain fatty acids are normally activated in

outer mitochondrial membrane, but this may also

occur at the surface of the endoplasmic reticulum.

002 2 The enzyme acyl-CoA synthetase, also called acyl-

CoA ligase or fatty acid thiokinase, catalyzes the

formation of a thiol ester bound between the fatty

acid and the thiol group of coenzyme A (eqn (1)).

Fatty acid þ ATP þ CoA-SH !Fatty acyl-CoA

þAMP þ 2Pi ð1Þ

0023 The reaction is accompanied by the hydrolysis of

ATP to form AMP and pyrophosphate. The pyro-

phosphate is rapidly hydrolyzed by inorganic

pyrophosphatase to two molecules of phosphate,

and the synthetase reaction is strongly promoted.

0024 The long-chain acyl-CoA derivatives cannot be

transported into the mitochondria matrix directly.

They must be converted to acylcarnitine derivatives

and then transported through the inner membrane of

the mitochondrion. This transport system consists of

the enzyme carnitine palmitoyltransferase I (CPTI)

localized in the mitochondrial outer membrane, of

an integral inner membrane protein the carnitine:a-

cylcarnitine translocase, and of the enzyme carnitine

palmitoyltransferase II localized on the matrix side

of the inner membrane as shown in Figure 1. The

enzyme CPTI catalyzes the formation of the O-

acylcarnitine, which is transported across the inner

membrane by a translocase. Inside the mitochondria,

the enzyme carnitine palmitoyltransferase II (CPTII)

transfers the fatty acyl group back to CoA and obtain

fatty acyl-CoA.

b-Oxidation Reactions

0025Once inside the mitochondrial matrix, the fatty acyl-

CoA is catalyzed by the enzymes in the b-oxidative

pathway, resulting in acetyl-CoA production. Energy

produced in the b-oxidation of fatty acids and the

oxidation of acetyl-CoA in the tricarboxylic acid

cycle is used to generate ATP via oxidative phos-

phorylation. The fatty acid oxidation begins with

the oxidation of the carbon that is in ‘b’ position to

the carboxyl carbon, and so this process has come to

be known as b-oxidation.

0026The mitochondrial b-oxidation of saturated fatty

acid acids proceeds by repeated cycles of four

reactions (flavin adenine dinucleotide (FAD)-linked

dehydrogenation, hydration, nicotinamide adenine

dinucleotide (NAD)

-linked dehydrogenation, hy-

dration, NAD

-linked dehydrogenation, and thio-

lysis) with chain shortening being achieved by the

successive cleavage of a C

unit as acetyl-CoA at

each cycle until the substrate has been completely

converted in acetyl-CoA. This is catalyzed by the

sequential action of four enzymes families (acyl-CoA

dehydrogenase, enoyl-CoA hydratase, l-hydroxy-

acyl-CoA dehydrogenase, and l-ketoacyl-CoA thio-

lase) each with a different substrate specificity for

short-, medium-, and long-chain acyl-CoAs.

0027As shown in Figure 2, the first reaction is catalyzed

by acyl-CoA dehydrogenase, a flavoprotein that is

present as a family of three enzymes that differ in

their specificity for the length of acyl-CoAs. Their

mechanism involves the oxidation of Ca–Cb bound

L-carnitine Fatty acyl-CoA CoA-SH O-acylcarnitine

Intermembrane

space

Carnitine:acylcarnitine

translocase

O-acylcarnitine CoA-SH Fatty acyl-CoA L-carnitine

Mitochondrial matrix

CPT-I

CPTII

fig0001 Figure 1 Transport into mitochondria of fatty acid.

FATTY ACIDS/Metabolism 2303

to form a trans double bond. During the oxidation of

the fatty acid, the FAD is reduced to FADH

, and the

electrons are transfered to an electron transfer flavo-

protein (ETF). Reduced ETF is reoxidized by a

specific oxidoreductase that donates electrons to the

electron transport chain at the level of coenzyme Q.

The next past is a hydrogenation reaction, catalyzed

by the ligase enoyl-CoA hydratase that saturates the

new double bond by the addition of a hydroxyl group

in the beta position. At least three enoyl-CoA hydra-

tase activities are known. These enzymes present

stereospecific and specifically converted trans-enoyl-

CoA derivates to l-b-hydroxyacyl-CoA. The fourth

reaction cleaves the b-keto ester, yielding one mol-

ecule of acetyl-CoA and a fatty acyl-CoA shortened

in two carbons.

0028 The repetitions of this cycle with the shortened

fatty acyl-CoA achieve the complete b-oxidation of

fatty acid. At the final step of this cycle, a fatty acid

with an even number of carbons yields two molecules

of acetyl-CoA.

0029 Fatty acids with an odd number of carbon atoms

are rare in mammals but are common in plants and

marine organisms. Humans and animals, whose diets

include these food sources, metabolize odd-carbon

fatty acids via the b-oxidation pathway. The final

product of b-oxidation in this case is the 3-carbon

propionyl-CoA instead of acetyl-CoA. Three special-

ized enzymes then carry out the reaction that converts

propionyl-CoA to succinyl-CoA, a TCA cycle inter-

mediate that may be oxidized to CO

0030The oxidation of polyunsaturated fatty acids in-

volves the action of two additional mitochondrial

enzymes NADPH (nicotinamide adenine dinucleotide

phosphate)-linked enoyl-CoA isomerase and D

–

enoyl-CoA reductase. They are needed to handle the

cis-double bonds of naturally occurring fatty acids.

Other Aspects of Fatty Acid Oxidation

0031Peroxisomes also have a system for the limited

b-oxidation of long-chain fatty acids to short-chain

acyl-CoA esters and acetyl-CoA. This short-chain

product must be transferred to the mitochondria for

further breakdown. Peroxisomal b-oxidation is

similar to mitochondrial b-oxidation, except that

the initial double-bond formation is catalyzed by an

FAD-dependent acyl-CoA oxidase.

0032In microsomes, unsaturated fatty acids are oxidized

to form eicosanoids and epoxy and hydroxy-fatty

acids. Some of these oxidative steps yield regulatory

molecules involved in cell signaling. For example,

arachidonic acid released from the sn-2 position

of the membrane phospholipids by the action of

phospholipase A

provides a substrate for cyclooxy-

genaxes, lipoxygenase, or monooxygenase.Cycloox-

ygenase and lipoxygenase products of arachidonic

acid (20:4, n-6) produce eicosanoids as prosta-

glandins, thromboxanes, and leukotrienes. These

eicosanoids play a critical role coordinating physio-

logical interactions among cells and have an influence

in a wide variety of functions, including those of the

central nervous system and the contraction of smooth

muscles. They also inhibit the mobilization of fatty

acids from adipose tissue, have an antiinflamatory

effect and modify the blood pressure, aggregation of

blood platelets, and cardiac function.

0033Branched-chain fatty acids are oxidized by

a-oxidation pathway. The CoA ester of this metabolic

pathway can undergo b-oxidation in the normal way.

Regulation of Fatty Acid Oxidation

0034Acetyl-CoA formed by mitochondrial oxidation can

be oxidized by the citrate cycle. The complete oxida-

tion of fatty acids in peripheral tissues is therefore

a major source of metabolic energy and heat in

humans. In liver, most of the acetyl-CoA formed by

b-oxidation is converted to ketone bodies (acetoace-

tate and 3-hydroxybutyrate), which are exported as

metabolic fuels for extrahepatic tissues. Peroxisomal

b-oxidation in the liver is less pronounced than in

mitochondria, but it has a key role in metabolizing

some very-long-chain fatty acids, although it is

Fatty acyl-CoA

FAD

FADH

Acyl-CoA

dehydrogenase

trans ∆

−Enoil-CoA

Enoyl-CoA

hydratase

L-β-hydroxyacyl-CoA

L-hydroxyacyl-CoA

dehydrogenase

NAD

NADH + H

β-Cetoacyl-CoA

Thiolase

CoA-SH

Acetyl-CoA

Fatty acyl-CoA

(Shortened by two carbons)

fig0002 Figure 2 b-Oxidation of saturated fatty acids.

2304 FATTY ACIDS/Metabolism

not directly linked to ATP synthesis. The rate of b-

oxidation is adjusted to physiological needs. This

sequence of events has two potential sites of regula-

tion, (a) transport of fatty acids into the cell, and (b)

enzymatic regulation.

0035 Fatty acid transport Long-chain fatty acids can be

transferred passively across mammalian cell mem-

branes. A simple diffusion process becomes signifi-

cant at higher molar ratios of fatty acid to albumin as

the concentration of free fatty acid in solution is

increased. However, under physiological conditions

of low fatty acid to albumin ratios in the circulation,

the major fraction of uptake appears to be mediated

by a protein component. Therefore, the plasma-

membrane-associated and cytoplasmic fatty-acid-

binding proteins are involved in cellular fatty acid

uptake, transport, and metabolism in tissues. These

binding proteins may also act modulate the metabol-

ism of long-chain fatty acids implicated in the regula-

tion of cell growth and other cellular functions.

0036 An acute increase in fatty acid concentration causes

a corresponding increase in fatty acid uptake without

necessarily increasing fatty acid oxidation. Thus,

fatty acid oxidation is more likely to be regulated by

factors inside the cell than by limitations in transport.

0037 The FABP exists within both the cytosol and

nucleus, which suggests that fatty acids or fatty

acid-CoA may be in the nucleus and act as ligands

that regulate the activity of specific transcription

factors.

0038 Enzymatic regulation When plasma FFAs enter the

cells, the first important step in their oxidation is the

formation of fatty-acyl-CoA. The enzymatic regula-

tion of CPT-I will then determine whether the fatty-

acyl-CoAs will be transferred into the mitochondria

for subsequent oxidation.

0039 The reaction catalyzed by CPT-I has been con-

sidered to be rate-limiting. CPT-I is subject to regula-

tion at the transcriptional level and to acute control

by malonyl-CoA. Thus, the N-terminal domain of

CPT-I is essential for malonyl-CoA inhibition.

0040 Malonyl-CoA, which is synthesized by acteyl-CoA

carboxylase, is an essential metabolic intermediate in

the regulation of fatty acid oxidation. A decrease in

malonyl-CoA level results in an increase in CPT-I

mediated fatty acid uptake into the mitochondria.

As fluctuations in tissue malonyl-CoA content are

parallel with changes in acetyl-CoA carboxylase

activity, which in turn is under the control of 5

AMP-activated protein kinase, the CPT-I/malonyl-

CoA system is part of a fuel-sensing gauge, turning

fatty acid oxidation on and off, depending on the

tissue’s energy demand.

0041No allosteric regulation or control of their activ-

ities by covalent modification of the other enzymes of

the b-oxidation pathway appears to have been de-

scribed, and it is now recognized that flux control of

flux through a pathway is shared between all the

enzymes involved, although their individual flux-

control coefficients may be very different.

Fatty Acid Biosynthesis. Lipogenesis

0042Long-chain fatty acids are essential constituents of

membrane lipids and are important substrates for

energy metabolism of the cell. When total energy

intake is in excess of the energy used, fatty acids and

triacylglycerol are synthesized.

0043The synthesis of fatty acids de novo is achieved

by the sequential condensation of two-carbon units

derived initially from acetyl-CoA.

0044Palmitate, the most abundant acid, is synthesized

de novo from acetyl-CoA, by acetyl-coA carboxylase

(ACC) and fatty acid synthase (FAS) in the cytoplasm.

0045ACC catalyzes the carboxylation of acetyl-CoA to

malonyl-CoA in an ATP-dependent manner. The re-

action catalyzed by this enzyme is shown in Figure 3.

0046Two forms of ACC have been identified. The

enzyme that is involved in the synthesis of long-

chain fatty acids has a molecular weight of 265 kDa,

and the other isoform, with a molecular weight of

275–280 kDa, may be involved in the regulation of

mitochondrial oxidation of fatty acids.

0047FAS plays the central role in de-novo lipogenesis in

mammals, catalyzing all reaction steps in the conver-

sion of acetyl-CoA and malonyl-CoA to palmitate by

enzymatic reactions catalyzed by FAS (Figure 4).

0048The reaction of FAS involves increasing the length

of the acetyl group by C

units derived from malonyl-

CoA in a stepwise and sequential manner. For in-

stance, in the synthesis of palmitate, there are over

40 steps with at least 30 acyl intermediates. A protein

known as acyl carrier protein (ACP) with its 4

phosphopantetheine prosthetic group was identified

as the coenzyme that binds all acyl intermediates as

thioester derivatives.

0049Seven enzymes and reactions are involved in the

synthesis of palmitate, as shown in Figure 5. These

reactions are essentially the same in all organisms.

Acetyl and malonyl are introduced as acyl carrier pro-

tein conjugates (reactions 1 and 2). Decarboxylation

HCO

+ ATP + E

Biotin E

Biotin

+ ADP + P

(A)

Biotin

+ Acetyl-CoA Malonyl-CoA + E

Biotin(B)

−

fig0003Figure 3 Reactions catalyzed by acetyl-coenzyme A carboxy-

lase.

FATTY ACIDS/Metabolism 2305

drives the b-ketoacyl-ACP synthase and results in the

addition of two carbon units to the growing chain

(reaction 3). The b-ketoacyl derivative is reduced in

three consecutive steps (reactions 4–6) to the satur-

ated acyl derivative, which then acts as a primer

for further elongation and reduction cycles to yield

ultimately a palmitoyl derivative. The latter is either

hydrolyzed to free palmitate (reaction 7), as in animal

cells and bacteria, or transferred to CoA-SH to form

palmitoyl-CoA, as in yeast, or utilized directly in the

triacylglycerol and phospholipid synthesis.

0050 In animal cells, the component enzymes of fatty

acid synthesis are covalently linked on a single poly-

peptide chain. From the N-terminus of FAS to its

C-terminus, amino acids encoding b-ketoacyl syntha-

tase, acetyl-CoA transacylase, malonyl-CoA trans-

acylase, dehydratase, enoyl reductase, b-ketoacyl

reductase, acyl carrier protein, and thioesterase activ-

ities are organized into discrete domains in the order

indicated. This is in contrast to bacterial and plant

FAS, which are multienzyme complexes consisting

of discrete monofunctional enzymes and fungal FAS,

which has functional components that are distributed

between two nonidentical polypeptides.

0051 The most important feature of animal FAS is its

multifunctional character. The animal FAS represents

one of the more complex multifunctional polypeptide

structures discovered to date because a single poly-

peptide structure contains all the catalytic compon-

ents required to direct the 37 reactions that lead to the

formation of palmitic acid from acetyl and malonyl-

CoA. The functional enzyme is a homodimer of the

250-kDa subunits and contains, in separate domains,

the seven different catalytic activities and the site

for the prosthetic group, 4

-phosphopantetheine, of

the acyl carrier protein (ACP). The multifunctional

nature of the subunits and their head-to-tail organiza-

tion produce a highly efficient enzyme complex

capable of carrying out multiple reactions leading to

the synthesis of a palmitate molecule from one acteyl

and seven malonyl moieties. This multifunctional

organization of FAS in vertebrates was probably

selected in the course of evolution, because it is

more efficient and because the partial activities are

more easily regulated in a coordinated fashion. The

substrates for each reaction can be channeled to the

active center of the subsequent enzymatic step within

the same polypeptide, thus providing a high efficiency

in long-chain fatty acid synthesis. Moreover, regulat-

ing production of the single polypeptide has an effect

at all the catalytic steps in a concerted manner.

Additional Elongation

0052Palmitate is the primary product of the fatty acid

synthase, but the cells may synthesize many other

fatty acids. Shorter chains can be made easily if the

chain is released before it reaches 16 carbons in

length. Longer chains are made through special

elongation reactions, which occur both in the mito-

chondria and at the surface of the endoplasmic reticu-

lum. The mitochondrial reactions involve addition

and subsequent reduction of acetyl units. The endo-

plasmic reticulum reactions involve the addition of

two-carbon units at the carboxyl end of the chain

by means of oxidative decarboxylations involving

malonyl-CoA.

Introduction of a Single

Cis

Double Bond

0053Prokaryotes and eukaryotes are able to introduce an

unsaturation (one or more double bond) in a fatty

Enzyme Reaction

Acetyl-CoA + ACP-SH Acetyl-ACP + CoA-SH

Malonyl-CoA + ACP-SH Malonyl-ACP + CoA-SH

Acetyl-ACP + synthase-SH acetyl-synthase + ACP-SH

Acetyl-synthase + Malonyl-ACP Acetoacetyl-ACP + CO

+ synthase-SH

Acetoacetyl-ACP + NADPH + H

D-Hydroxybutyryl-ACP + NADP

D-Hydroxybutyryl-ACP Crotonyl-ACP + H

Crotonyl-ACP + NADPH + H

Butyryl-ACP + NADP

Palmitoyl-ACP + H

O Palmitate + ACP-SH

(1) Acetyl transacylase

(2) Malonyl transacylase

(3) β-Ketoacyl synthase

(condensing enzyme)

(4) β-Ketoacyl reductase

(5) β-Hydroxyacyl dehydratase

(6) Enoyl reductase

(7) Thioesterase

fig0005 Figure 5 Reactions and component enzymes of fatty acid synthase.

Acetyl-CoA + 7 Malonyl CoA + 14 NADPH + 14 H

+ 7 ATP + H

O Palmitic ac. + 8 CoA + 14 NADP

+ 7 ADP + 7 P

fig0004 Figure 4 Reaction catalyzed by fatty acid synthase.

2306 FATTY ACIDS/Metabolism

acid. Double bonds in fatty acids are predominantly

of the cis (or Z) configuration. Many prokaryotes

introduce double bonds into fatty acids anaerobically,

whereas eukaryotes have adopted an O

-dependent

pathway. So, the advent of an aerobic environment

several billion years ago allowed eukaryotes, cyano-

bacteria, and some bacilli to desaturate the methyl-

ene groups of long-chain fatty acids using enzymes

called fatty acid desaturases. The transition from

anaerobic to aerobic respiration yielded more than

an order of magnitude of energy efficiency, leaving

a surplus available for processes such as oxidative

desaturation. In addition, the ability to regulate

membrane fluidity controlling the number of double

bonds in fatty acids within the membrane in response

to changing temperatures probably conferred a

selective advantage to organisms capable of aerobic

desaturation.

0054 The anaerobic biosynthesis of unsaturated fatty

acids involves dehydration of a hydroxy substrate

followed by trans–cis isomerization of the double

bond. The aerobic reaction can occur anywhere in the

fatty acid chain without the need to activate the desired

bond toward dehydrogenation. Fatty acid desatura-

tion involves an enzymatic reaction in which a double

bond is introduced into an acyl chain, and a molecule

of oxygen is completely reduced to water. Two classes

of fatty acid desaturase enzymes capable of convert-

ing saturated to monounsaturated fatty acids are

known, one soluble and the other membrane-bound.

Desaturase enzymes need the presence of NADH and

oxygen, and two other proteins, cytochrome b

and

cytochrome b

reductase, are involved.

0055 Mammals require polyunsaturated fatty acids but

must acquire them in their diet. As such, they are

referred to as essential fatty acids (linoleic and lino-

lenic acid). However, mammals can add additional

double bonds to unsaturated fatty acids from their

diets. Three major groups of dietary fatty acids are

oleic acid, linoleic acid, and linolenic acid. These fatty

acids serve as precursors for the biosynthesis of a

long-chain polyunsaturated fatty acid with carbon

lengths of C20/C22. These biosynthetic pathways

consist of a series of desaturation and chain elonga-

tion steps. Desaturation occurs only toward the carb-

oxylic end of fatty acids in mammalian tissues, and

there is no direct crossover among unsaturated fatty

acids from one group to another.

Regulatory Control of Fatty Acid Biosynthesis

0056 Variations in the composition and quantity of the diet

and rates of de novo fatty acid and triacylglycerol

synthesis are tightly regulated by nutritional and

hormonal status to meet the body’s requirement for

lipid and energy storage.

0057The activity of the lipogenic pathway is dependent

on nutritional conditions, both in the liver and in the

adipose tissue. Consumption of a diet rich in carbo-

hydrates stimulates the lipogenic pathway, whereas

starvation or consumption of a diet rich in lipids and

poor in carbohydrates decreases its function. Flux

through the lipogenic pathway depends on the avail-

ability both of lipogenic substrates and of cofactors

such as NADPH produced by the pentose phosphate

pathway. Regulation of the activity of the lipogenic

enzymes involves both short-term and long-term

mechanisms.

0058ACC is the rate-limiting enzyme in the biosynthesis

of fatty acids. The ACC activity and the rate of fatty

acid synthesis fluctuate rapidly in response to various

factors such as hormonal, dietary, developmental,

and genetic factors. In the regulation of ACC, short-

term changes in the enzymatic activity of ACC are

through allosteric regulation, phosphorylation/

dephosphorylation events and polymerization/de-

polymerization mechanisms linked to the presence

of specific metabolites as Ca. However, long-term

regulation mechanisms, particularly those acting at

the gene level of ACC, are controlled at a transcrip-

tion level and involve changes in the concentrations of

regulated enzymes, for example, those observed in

animals being fasted and then fed.

0059The expression of the FAS gene is also highly

dependent on the nutritional conditions in liver and

adipose tissue. Expression of the gene is barely detect-

able in starved animals and is stimulated by refeeding

with a high-carbohydrate, fat-free diet.

0060Thus, the amount of carbohydrate in the diet

appears to be instrumental in turning on transcription

of genes coding for lipogenic enzymes in liver and

adipose tissue. Rates of expression of the genes for

FAS and ACC are stimulated by glucose in adipose

tissue in vivo and in vitro. Expression of FAS and

ACC is stimulated in the liver and of ACC in a pan-

creatic b-cell line. In each case, regulation involves

stimulation of transcription, and to stimulate gene

transcription, glucose must be metabolized. To date,

the role of insulin, either direct or indirect, is still

disputed. Indeed, insulin is reported to restore lipo-

genic enzyme gene expression in diabetic rats, and

glucagon (via cAMP) inhibits expression of the genes

for lipogenic enzymes. In adipose tissue, insulin in-

creases indirectly the expression of FAS and ACC by

stimulating glucose transport.

0061Although normal tissues have low levels of fatty

acid synthesis, a number of recent studies have

demonstrated high levels of FAS expression in a

wide variety of human cancers, including carcinoma

of the colon, prostate, ovary, endometrium, and

breast. The widespread expression of FAS in human

FATTY ACIDS/Metabolism 2307