Chapter 90 Fatty Acid Metabolism

Although a growing body of research documents the critical importance of fatty acids for maintaining health, common food choices in modern society do not lead to appropriate levels or balances of these nutrients. Years of negative associations of dietary fat with calories, cholesterol, and cancer have resulted in a general public attitude that foods containing fats should simply be avoided. Many food manufacturers have taken advantage of this attitude by modifying fat content and labeling, wherever possible, to tout “low-fat” foods. Advertisements for such foods further instill the notion that dietary fat is bad. Amid the clamor over the largely mistaken problems associated with dietary fats, many problems have been created by the large-scale use of modified fats by food suppliers. Individuals do not feel the effects of abusing dietary fats for the short term because of the presence of many protective mechanisms that make health threats from fat abuse an insidious process.

Modern diets of fast foods and packaged dinners tend to be rich in saturated fats and hydrogenated oils and lacking in essential fatty acids (EFAs). We now know that the amount and type of dietary fat play major roles in maintaining health. Some saturated fatty acids stimulate cholesterol formation, but most do not.

The old concept of three EFAs has been replaced by recognition of critical roles for multiple polyunsaturated fatty acids (PUFAs). Dietary fats simultaneously provide the major cellular energy source, control the passage of compounds into and out of cells, determine the integrity of nerve tissue, and serve to form powerful hormones.

The essential hormone function is mediated by some special fatty acids that affect energy flow, cell division, immune responses, and many other body controls. These critical fatty acids are used to make powerful tissue-specific compounds called eicosanoids. Figure 90-1 illustrates the various roles of fatty acids. This chapter discusses more about these functions after some basic fatty acid relationships are explained.

FIGURE 90-1 Metabolic roles of fatty acids.

Fatty Acid Structure and Metabolism

About 30 structural isomers and homologs of fatty acids occur in human tissues. They are named in various ways, including those with Latin prefixes such as penta– and hexa– for the number of carbon atoms. These are the chemical names approved by the International Union of Pure and Applied Chemists. Many also have common names. Because common names are in widest use among clinicians, they are used here. Table 90-1 provides a lexicon of fatty acid terms.

TABLE 90-1 Lexicon of Fatty Acid Terms

TERM OR ABBREVIATION	DEFINITION OR EXPLANATION
AA	Arachidonic acid
ALA	Alpha-linolenic acid
Alpha-linolenic acid	Delta 9,12,15 octadecatrienoic acid; 18:3 ω-3
Arachidonic acid	Delta 5,8,11,14 eicosatetraenoic acid; 20:4 ω-6
Beta-oxidation	The mitochondrial metabolic pathway whereby fatty acids are converted into acetyl CoA, which enters the citric acid cycle to ultimately yield adenosine triphosphate. The carbon atoms of the fatty acid are oxidized to carbon dioxide.
Carnitine	The molecule to which fatty acids are attached in the process of their enzyme-mediated entry into the mitochondrial matrix. This enzyme is inhibited by malonyl CoA formed during fatty acid synthesis from carbohydrates.
Cerebronic acid	The 2-hydroxy derivative of lignoceric acid (24:0); found in glycosphingolipids in the brain
Cervonic acid	Another name for docosahexaenoic acid
cis	Geometrical isomer in which two groups are on the same side of a double bond
Clupanodonic acid	Another name for δ-7,10,13,16,19-docosapentaenoic acid (DPA3), an ω-3 series, long-chain, highly unsaturated fatty acid; found in fish oils and phospholipids in the brain
Delta	Used to describe the position of double bonds relative to the carboxyl end of a fatty acid
Desaturase	Tightly bound to the endoplasmic reticulum membrane, this enzyme, in association with cytochrome b5 and cytochrome b5 reductase, uses reduced nicotinamide adenine dinucleotide and oxygen to introduce double bonds into fatty acids. There are at least four separate desaturases, named according to the position of inserted double bonds. Delta-9-desaturase, δ-6-desaturase, and δ-5(4) desaturase act on fatty acetyl CoA thioesters, always inserting double bonds between the thioester bond (carboxylate group) and the double bond closest to it, leaving a three-carbon gap. Activities of these enzymes fluctuate according to dietary fat intake to maintain optimal fluidity state of the membrane lipids. Their concentrations decrease in starvation and increase greatly on refeeding carbohydrates. They are suppressed when dietary unsaturated fatty acid intake (including trans isomers) is high.
DGLA	Dihomogammalinolenic acid
Dihomogammalinolenic acid	Delta 8,11,4 eicosatrienoic acid; 20:3 ω-6
DHA	Delta 4,7,10,13,16,19 docosahexaenoic acid; 22:6; an ω-3 series long-chain, highly unsaturated fatty acid; found in fish oils and the phospholipids in the brain (also known as cervonic acid)
Dienoic	Contains two double bonds
EFA	Essential fatty acid
Eicosanoid	A product of the specific, enzyme-directed oxidation of polyunsaturated fatty acids containing 20 (eicosa)carbons. This term encompasses the prostaglandins, thromboxanes, and leukotrienes.
Eicosapentaenoic acid	Delta 5,8,11,14,17 eicosapentaenoic acid; 20:5 ω-3; one of the most abundant fatty acids in fish oils
Elongase	An enzyme that adds 2-carbon units (acetate) to the carboxyl end of an existing saturated or unsaturated fatty acid. Mitochondrial form uses acetyl CoA, whereas endoplasmic form has malonyl CoA as substrate.
EPA	Eicosapentaenoic acid
Gamma linolenic acid	Delta 6,9,12 octadecatrienoic acid; 18:3 ω-6
GLA	Gamma-linolenic acid
HUFA	Highly unsaturated fatty acid; generally having five or six double bonds
LA	Linoleic acid
Lauric acid	Tetradecanoic acid; C12:O; first isolated and identified from the laurel plant
LCP	Long-chain polyunsaturated fatty acid
Linoleic acid	Delta 9,12 octadecadienoic acid; 18:2 ω-6
Meads acid	Delta 5,8,11 eicosatrienoic acid; 20:3 ω-9. This compound is not normally produced in appreciable amounts due to the preferential loading of the desaturase enzymes with the more strongly binding essential fatty acids and their metabolic products. It accumulates, however, in essential fatty acid deficiency, making it a marker for this condition.
Monoenoic	Containing one double bond
MUFA	Monounsaturated fatty acid
Omega	Used to describe the position of double bonds relative to the methyl end of a fatty acid
P + M/S ratio	Polyunsaturated + monounsaturated to saturated fatty acid ratio
P/S ratio	Polyunsaturated-to-saturated fatty acid ratio
Phospholipase A2	An enzyme that catalyzes the hydrolysis of the fatty acid ester from position 2 of phosphoglycerides. Dependent on calcium, this enzyme is responsive to intracellular calcium, calmodulin, etc. It releases primarily polyenoic fatty acids (arachidonic acid, etc.) from membranes for eicosanoid synthesis.
PUFA	Polyunsaturated fatty acid
Phosphatide	Diacylglycerol phosphate, to which various groups may be attached through phosphoester linkage; the principal components of cell membranes
Polyenoic	Containing two or more double bonds
Saturated fatty acid	A fatty acid in which all of the carbon atoms except for the carboxyl carbon are fully hydrogenated as −CH2− (and −CH3)
Stearidonic acid	Delta 6,9,12,15 octadecatetraenoic acid; 18:4 ω-3; a product of elongation of ALA and a precursor to EPA. A good source is black currant seed oil.
Timnodonic acid	Another name for EPA or 20:4 ω-6
Trans	Geometrical isomer in which two groups are on opposite sides of a double bond
Unsaturated fatty acid	A fatty acid in which two or more adjacent pairs of carbon atoms are lacking hydrogen atoms, having instead an additional carbon–carbon bond or double bond
δ	The Greek letter delta
ω	The Greek letter omega

CoA, coenzyme A.

Fatty acids containing the maximum number of carbon–hydrogen bonds are called saturated. They have a higher energy or caloric yield than corresponding unsaturated fatty acids (UFAs). They are present as major components of most foods and are high in manufactured foods such as candy bars. The most abundant members in human tissues are those that are 14 (myristic), 16 (palmitic), or 18 (stearic) carbons long. The elongation process can be repeated to yield members that are 20, 22, and 24 carbons long.

Three major families of UFAs are found in human tissues: the ω-9, ω-6, and ω-3 UFAs (or n-9, n-6, and n-3). The ω-6 and ω-3 PUFAs are defined by the position of the double bond closest to the terminal methyl group of the fatty acid molecule. In the ω-6 family, the first double bond occurs between the sixth and seventh carbons from the methyl group end of the molecule, whereas in the ω-3 family, the first double bond occurs between the third and fourth carbons (Figure 90-2 provides naming conventions).

FIGURE 90-2 Naming conventions for unsaturated fatty acids.

The older δ naming scheme gives the positions of all double bonds, counting from the carboxyl or number 1 carbon. The ω scheme takes advantage of the fact that the double bonds are always separated by three carbons and simply gives the total length and number of double bonds separated by a colon. The number after the ω symbol gives the position of the first double bond counting from the ω-1 carbon.

Fatty acids can be synthesized from acetyl coenzyme A (CoA) derived from carbohydrate, protein, and other nonlipid sources. This pathway produces saturated fatty acids, predominantly palmitic acid (16:0). Palmitic acid can be desaturated, forming palmitoleic acid of the ω-7 class of UFAs. Palmitic acid can also be lengthened to stearic acid (18:0) and desaturated to form oleic acid of the ω-9 class. The ω-6 and ω-3 classes of UFAs are derived from dietary PUFAs. These classes can be further lengthened and desaturated. None of the four ω classes of UFAs, however, is interconvertible. These reactions can be repeated in various combinations, giving an array of saturated and UFAs for use in the essential functions of tissue maintenance.

The desaturase enzymes function to place double bonds at positions up to nine carbons from the carboxyl end of the molecules. When you count from the other end, the position varies, depending on the length of the fatty acid. Thus, for stearic acid with 18 carbons, a desaturase can form a double bond nine carbons from the carboxyl end, which is also nine carbons from the methyl end (18 − 9 = 9). These differences become important because the type of eicosanoid hormones that can be formed later depends on the position of the first double bond from the methyl end.

The geometry of desaturase enzymes will not allow insertion farther than nine carbons (δ-9) from the carboxyl group. Thus, linoleic acid (LA; δ-9, 12) cannot be synthesized in humans. Fatty acids of various chain lengths can act as desaturase substrates, as well as those that already possess double bonds at other positions. Figure 90-3 shows the products of the δ-9 desaturase acting on three saturated fatty acids.

FIGURE 90-3 Formation of monounsaturated fatty acids.

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