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

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.

The activity of the desaturase enzymes is critical for maintaining the ratio of saturated and unsaturated components in cell membranes. Tumor tissue and virus-transformed cells have a higher content of UFAs, especially oleic acid, which increases relative to the amount of stearic acid. Such shifts increase the metabolic rates of many lipid-dependent enzymes and are associated with a higher capacity for cell division.¹ Individuals with recurrent tumors may already have too much oleic acid relative to stearic acid, and encouraging a diet high in olive oil or other highly UFAs may be contraindicated.

In the tissues of plants and higher animals, the insertion of double bonds always results in the cis geometry. The phrase “partially hydrogenated vegetable oil” on food labels indicates that a natural oil has been chemically modified in a process that converts some of the cis UFAs to the trans form. Oleic acid is changed into its trans isomer, elaidic acid, which is the most abundant trans fatty acid in most hydrogenated oils. In human metabolism, trans unsaturated fat behaves similar to saturated fat, meaning that their accumulation tends to increase the risk of heart disease. Adverse effects of trans fatty acids on high-density lipoprotein or low-density lipoprotein cholesterol are well documented in medical research literature.^2–4

Interference with eicosanoid production is also suspected, and research in the area of health risks of trans fatty acids is accelerating. Trans fatty acid levels in cell membranes are determined by dietary intake of hydrogenated oils.⁵ A person eating a doughnut for breakfast (3.19 g of trans fatty acids), a small order of French fries with lunch (3.43 g), two teaspoons of margarine on bread with dinner (1.24 g), and two cookies for a snack (1.72 g) would ingest a total of 9.58 g of trans fatty acids, enough to negate the serum cholesterol-lowering effects of a decrease in saturated fat of 10% of total energy intake.⁶

Dietary PUFAs are largely composed of the ω-6 family (e.g., linolenic acid [LA]), which is abundant in vegetable seed oils, and the ω-3 family (e.g., α-linolenic acid [ALA]), which is high in vegetable leaves, flaxseeds, walnuts, canola, and modest in soybean oil.⁷ Table 90-2 lists other members of these classes. When the diet supplies adequate LA and ALA, they may be used to form the other members in their classes by desaturation and elongation reactions.

TABLE 90-2 Polyunsaturated Fatty Acid Families

The δ-6 desaturase enzyme acts as a gateway for the flow of fatty acids through the desaturation and elongation pathway. Although it can act on any long-chain fatty acid, the substrate binding affinity increases greatly with the number of double bonds already present. Thus, 18:3 binds stronger than 18:2, which binds stronger than 18:1. The result is that ALA is quickly converted to eicosapentaenoic acid (EPA), whereas oleic acid is slowly converted into 20:3ω9 in the presence of appreciable amounts of either LA or ALA. When the two EFAs are absent, however, 20:3ω9 accumulates because the desaturase is free to act on oleic acid. Elevated 20:3ω9 (Mead or eicosatrienoic acid) is a marker that can be used to detect EFA deficiency.

The δ-6 desaturase enzyme requires a zinc ion for activity. For this reason, supplementing a patient with sources of LA and ALA does little good if zinc deficiency is present. The changes in body growth, organ weights, and lipid concentrations in plasma and liver produced by zinc deficiency are reversed by the addition of γ-linoleic acid (GLA)-rich primrose oil, but not LA-rich safflower oil, showing the role of zinc in the δ-6 desaturase enzyme.⁸ The enzyme is also inhibited by high concentrations of saturated fatty acids, monounsaturated acids, and trans fatty acids, all of which compete for the enzyme binding site and yield products that are of less significance to the cell.

The PUFAs impact health due to their conversion to compounds, collectively called eicosanoids, which possess extremely potent biological activities. Their functions of regulating blood vessel leaking, lipid accumulation, inflammation, and immune cell behavior are relevant to the initiation and progress of cardiovascular disease.⁹ These compounds, in turn, are used to amplify and balance signals to the organs, the blood clotting system, and the immune system.

Production of eicosanoid hormones is shown in Figure 90-4. The parent compounds are dihomogammalinolenic (DGLA), arachidonic acid (AA), and EPA, and the pathway uses the same cyclooxygenase enzyme for all three series of products. The relative concentrations of the three fatty acids present in the phospholipids of the cell membranes where the hormones are produced determine which product will predominate, due to substrate competition for the active site, as depicted in Figure 90-4. In a similar manner, the lipoxygenase enzyme initiates the sequence of reactions leading to leukotriene formation. The 2-series that is derived from AA is by far the most proinflammatory. The effects of GLA and DGLA on rheumatoid arthritis and many other inflammatory diseases are mediated via this mechanism. Because dietary intake is a primary determinant of the fatty acids that enter this pathway, there is a direct link between the balance of specific fats in the diet and inflammatory responses and other local control processes. Long-term health maintenance is highly dependent on proper balance of dietary fatty acids.

FIGURE 90-4 Fatty acid relationships to eicosanoid formation.

It is no longer adequate simply to recommend the replacement of saturated fats with PUFAs. Balanced intake of n-3 and n-6 fatty acids, not just a high PUFA-to-saturated ratio, is required for optimal control of every tissue in the body.¹⁰ Chapter 14 discusses the interpretation of fatty acid testing and clinical interventions.

Control of Fatty Acid Supply and Distribution

Fatty acids are present in the diet in the form of triglycerides in solid fats or liquid oils and as phosphatides in cell membranes of whole foods. They are rarely present in nature as free fatty acids. Table 90-3 lists food sources of the more abundant fatty acids. Foods always contain complex mixtures of fatty acids with enrichment of any single fatty acid rarely exceeding 70%.

TABLE 90-3 Dietary Sources of Even-numbered Medium-chain and Long-chain Saturated Fatty Acids

Ingested fats are dispersed and digested by the action of bile acids and lipase enzymes. They pass into enterocytes along with cholesterol, where they are associated with proteins, becoming particles called chylomicrons. These are passed into the lymphatic system to flow directly through the heart into systemic circulation. Enzymes in capillary cell walls cause fatty acid transfer from chylomicrons, which become greatly reduced in size and return for uptake by the liver as chylomicron remnants. By this process, the fatty acids in foods become directly incorporated into the membranes of all tissues.

Because of the critical life-supporting functions in forming cell membranes and supplying energy sources and hormone controls, several mechanisms assure that the supply of fatty acids will be continuous, even during short intervals between meals. In the fasting state, fatty acids are either produced from carbohydrates or protein or mobilized from adipose stores. The liver handles the role of supply depot by forming another class of lipid-protein particles called very low-density lipoproteins. These particles deliver fatty acids and cholesterol to the tissues by mechanisms similar to those for chylomicrons, except that the remnant low-density lipoprotein particles are taken up in total by binding to receptor sites on cell surfaces. By ensuring a constant supply of fatty acids, the body controls one of the most critical materials for carrying out the various life-sustaining functions of growth and repair.

Effect of Low-Fat Diets

An individual on a low-fat, high-carbohydrate diet uses the fatty acid synthetic pathway extensively. As shown in Figure 90-5, this pathway requires citrate to leave the mitochondria to generate malonyl CoA. The resultant high concentrations of malonyl CoA inhibit the activity of the enzyme that is the gateway to fatty acid oxidation. For this reason, very low-fat diets do not result in weight loss nearly as quickly as one might expect. The burning of excess fat is actually inhibited by the high carbohydrate intake. In individuals with low body fat and good lean mass, high carbohydrate intake spares the use of fatty acids. In more sedentary individuals with lower rates of fatty acid oxidation, the medium-chain fatty acids that are otherwise so quickly used for energy may accumulate above normal levels in membranes.

FIGURE 90-5 Carbohydrate conversion to fat; inhibition of fatty acid oxidation.

Many other factors influence the rate of oxidation of fatty acids. Dramatically increased fatty acid oxidation occurs in starvation and diabetes mellitus with production of large amounts of ketone bodies that accumulate to give the ketoacidotic condition. Carnitine deficiency results in impairment of fatty acid oxidation and failure of gluconeogenesis, leading to hypoglycemia.

Fatty Acids and Human Diseases

Quantification of the approximately 30 fatty acids present in human tissues is now routinely available. Both deficiencies and excesses of individual fatty acids lead to metabolic problems. A brief discussion of a few highly relevant conditions affected by fatty acid intake is presented here (see Chapter 14 for additional discussion of specific fatty acid imbalances). Table 90-4 lists typical signs and symptoms of fatty acid abnormalities, and Table 90-5 lists some well-documented clinical applications of supplemental fatty acids.

TABLE 90-4 Signs and Symptoms Associated with Fatty Acid Abnormalities

DGLA, dihomogammalinolenic acid; FAs, fatty acids; GLA, γ-linolenic acid; Mn, magnesium; PUFA, polyunsaturated fatty acid; Se, selenium; Zn, zinc.

TABLE 90-5 Clinical Use of γ-linolenic Acid and α-linolenic Acid

X, moderate response; XX, strong clinical response.