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Chapter: Introduction to Human Nutrition: Nutrition and Metabolism of Lipids

Long-chain fatty acid metabolism

Synthesis of fatty acids occurs in the cytosol. It begins with acetyl-CoA being converted to malonyl-CoA by acetyl-CoA carboxylase, an enzyme dependent on biotin.

Long-chain fatty acid metabolism


Synthesis of fatty acids occurs in the cytosol. It begins with acetyl-CoA being converted to malonyl-CoA by acetyl-CoA carboxylase, an enzyme dependent on biotin. Malonyl-CoA and a second acetyl-CoA then condense via β-ketothiolase. This is subsequently reduced, dehydrated, and then hydrogenated to yield a four-carbon product that recycles through the same series of steps until the most common long-chain fatty acid product, palmitate, is produced (Figure 6.10). Acetyl-CoA is primarily an intramitochondrial product. Thus, the transfer of acetyl-CoA to the cytosol for fatty acid synthesis appears to require its conversion to citrate to exit the mitochondria before being reconverted to acetyl-CoA in the cytosol.


Figure 6.10 Principal steps in fatty acid synthesis. The individual steps occur with the substrate being anchored to the acyl carrier protein. SA, S-acyl carrier protein; SS, S-synthase.


There are three main features of long-chain fatty acid synthesis in mammals:

1  inhibition by starvation


2  stimulation by feeding carbohydrate after fasting


3  general inhibition by dietary fat.

Carbohydrate is an important source of carbon for generating acetyl-CoA and citrate used in fatty acid synthesis. Enzymes of carbohydrate metabolism also help to generate the NADPH needed in fatty acid synthesis. Acetyl-CoA carboxylase is a key control point in the pathway and is both activated and induced to polymerize by citrate. Acetyl-CoA carboxylase is inhibited by long-chain fatty acids, especially PUFAs such as linoleate. 

This is probably one important negative feedback mechanism by which both starva-tion and dietary fat decrease fatty acid synthesis. High amounts of free long-chain fatty acids would also compete for CoA, leading to their β-oxidation. Elongation of palmitate to stearate, etc., can occur in mitochondria using acetyl-CoA, but is more com-monly associated with the endoplasmic reticulum where malonyl-CoA is the substrate.


Humans consuming >25% dietary fat synthesize relatively low amounts of fat (<2 g/day). Compared with other animals, humans also appear to have a relatively low capacity to convert stearate to oleate and linoleate or α-linolenate to the respective longer chain polyunsaturates. Hence, the fatty acid profiles of most human tissues generally reflect the intake of dietary fatty acids; when long-chain n-3 PUFAs are present in the diet, this is evident in both free-living humans as well as in experimental animals. Neverthe-less, fatty acid synthesis is stimulated by fasting/ refeeding or weight cycling, so these perturbations in normal food intake can markedly alter tissue fatty acid profiles.




β-Oxidation is the process by which fatty acids are utilized for energy. Saturated fatty acids destined for β-oxidation are transported as CoA esters to the outer leaflet of mitochondria by FABP. They are then translocated inside the mitochondria by carnitine acyl-transferases. The β-oxidation process involves repeated dehydrogenation at sequential two-carbon steps and reduction of the associated flavoproteins (Figure 6.11). Five ATP molecules are produced during production of each acetyl-CoA. A further 12 ATP molecules are produced after the acetyl-CoA condenses with oxaloacetate to form citrate and goes through the tricarboxylic acid cycle.

Figure 6.11 Principal steps in β-oxidation of a saturated fatty acid. The steps shown follow fatty acid “activation” (binding to coenzyme A) and carnitine-dependent transport to the inner surface of the mito-chondria. Unsaturated fatty acids require additional steps to remove the double bonds before continuing with the pathway shown. FAD, flavin adenine dinucleotide; FADH reduced flavin adenine dinucleo-tide; R, 12 carbons.

The efficiency of fatty acid oxidation depends on the availability of oxaloacetate and, hence, concurrent carbohydrate oxidation. β-Oxidation of saturated fatty acids appears to be simpler than oxidation of unsaturated fatty acids because, before the acetyl-CoA cleavage, it involves the formation of a trans double bond two carbons from the CoA. In contrast, β-oxidation of unsaturated fatty acids yields a double bond in a different position that then requires further isomerization or hydrogenation. From a biochemical perspective, this extra step appears to make the oxida-tion of unsaturated fatty acids less efficient than that of saturated fatty acids. However, abundant in vivo and in vitro research in both humans and animals clearly shows that long-chain cis-unsaturated fatty acids with one to three double bonds (oleate, linole-ate, α-linolenate) are more readily β-oxidized than saturated fatty acids of equivalent chain length, such as palmitate and stearate. The oxidation of PUFA and monounsaturates in preference to saturates has potential implications for chronic diseases such as coronary artery disease because their slower oxida-tion implies slower clearance from the blood, thereby providing more opportunity for esterification to cho-lesterol and subsequent deposition in the vessel wall.

 In peroxisomes, fatty acid β-oxidation is a trun-cated process by which long-chain PUFAs are chain shortened. This peroxisomal detour has been identi-fied as an obligatory step in the endogenous synthesis of docosahexaenoate from eicosapentaenoate.

Odd-carbon long-chain fatty acids are relatively uncommon but, when β-oxidized, yield propionylCoA, the further β-oxidation of which requires biotin and vitamin B12 as coenzymes.

Ketogenesis and ketosis

Large amounts of free fatty acids inhibit glycolysis and the enzymes of the tricarboxylic acid cycle, thereby impairing production of oxaloacetate. When insufficient oxaloacetate is available to support the continued oxidation of acetyl-CoA, two acetyl-CoA molecules condense to form a ketone, acetoacetate. Acetoacetate can be spontaneously decarboxylated to form acetone, a volatile ketone, or converted to a third ketone, β-hydroxybutyrate. When glucose is limiting, ketones are an alternative source of energy for certain organs, particularly the brain. They are also efficient substrates for lipid synthesis during early postnatal development. Conditions favoring ketogenesis include starvation, diabetes, and a very high-fat, low-carbohydrate “ketogenic” diet.

Carbon recycling

Carbon recycling is the process by which acetyl-CoA derived from β-oxidation of one fatty acid is incor-porated into another lipid instead of completing the β-oxidation process to carbon dioxide. In principle, all fatty acids undergo this process to some extent but it is most clearly evident for two PUFAs, linoleate and α-linolenate. Carbon recycling captures the over-whelming majority of α-linolenate carbon, i.e., about 10 times more than is incorporated into docosahexae-noate, which remains in the body of suckling rats 48 hours after dosing with uniformly 13C-labeled α-lino-lenate. Carbon recycling of linoleate in the rat cap-tures similar amounts of the linoleate skeleton to those of arachidonate, the main desaturation and chain-elongation product of linoleate. Hence, carbon recycling appears to be a ubiquitous feature of the metabolism of PUFA, although its biological signifi-cance is still unclear.


Peroxidation (auto-oxidation) is the nonenzyme-cat-alyzed reaction of molecular oxygen with organic compounds to form peroxides and related breakdown products. PUFAs are particularly vulnerable to peroxi-dation at the double bonds. Initiating agents such as pre-existing peroxides, transition metals, or ultraviolet or ionizing radiation produce singlet oxygen. Singlet oxygen can then abstract hydrogen at the double bonds of polyunsaturates to produce free (peroxy) radicals, which abstract further hydrogens from the same or different fatty acids and propagate the peroxidation process. Eventually, this leads to termination by the formation of stable degradation products or hydro-peroxides (Figure 6.12). Trans isomers are frequently formed during the process. Hydroperoxides can form further hydroperoxy radicals or can be reduced by antioxidants, which contain thiol groups, i.e., glutathi-one and cysteine. Peroxidation of dietary fats gives rise to aldehydes, i.e., 2-undecenal, 2-decenal, nonanal, or octanal, which have a particular odor commonly known as rancidity.

Figure 6.12 Principal steps in peroxidation of a polyunsaturated fatty acid.

Since peroxidation is a feature of polyunsaturates, it is a potential hazard facing most membranes and dietary lipids. Antioxidants such as vitamin E are usually present in sufficient amounts to prevent or block peroxidation in living tissues. Humans and animals readily detect peroxidized fats in foods by their disagreeable odor and avoid them. However, modeling the effects of peroxides produced in vivo and in vitro is particularly challenging because lipid peroxidation undoubtedly is an important part of several necessary biological processes such as activa-tion of the immune response.

Desaturation, chain elongation, and chain shortening

One important characteristic of long-chain fatty acid metabolism in both plants and animals is the capacity to convert one to another via the processes of desatu-ration, chain elongation, and chain shortening.


Plants and animals use desaturases to insert a double bond into long-chain fatty acids. There are several desaturases, depending on the position in the acyl chain into which the double bond is inserted. Although myristate (14:0) and palmitate can be converted to their monounsaturated derivatives, myristoleate (14:1n-5) and palmitoleate (16:1n-7) respectively, commonly it is only the fatty acids of 18 or more carbons that undergo desaturation. The 9 desaturases in all organisms, except for anaerobic bac-teria, use oxygen and NADPH to introduce a cis double bond at carbons 9 and 10 of stearate. This is accomplished by an enzyme complex consisting of a series of two cytochromes and the terminal desatu-rase itself. The acyl-CoA form of fatty acids is the usual substrate for the desaturases, but fatty acids esterified to phospholipids can also be desaturated in situ.


All mammals that have been studied can convert stearate to oleate via 9 desaturase. However, in the absence of dietary oleate, young rats may have insuf-ficient capacity to sustain normal tissue oleate levels. Normal values depend on the reference, which can vary widely depending on the source and amount of oleate in the diet. Nevertheless, it is important to dis-tinguish between the existence of a given desaturase and the capacity of that pathway to make sufficient of the necessary product fatty acid. Hence, as with the long-chain polyunsaturates and, indeed, with other nutrients such as amino acids, it is important to keep in mind that the existence of a pathway to make a particular fatty acid or amino acid does not guarantee sufficient capacity of that pathway to make that product. This is the origin of the concept of “conditional essentiality” or “indispensability.” Both plants and animals are capable of desaturating at the 9–10 carbon ( 9 desaturase) of stearate, result-ing in oleate. However, only plants are capable of desaturating oleate to linoleate and then to α-lino-lenate. Once linoleate and α-linolenate are consumed by animals, their conversion to the longer chain PUFAs of their respective families proceeds primarily by an alternating series of desaturation ( 6 and 5 desaturases) and chain-elongation steps (Figure 6.13). Sequential desaturations or chain elongations are also a possibility, resulting in a large variety, though low abundance, of other PUFAs.


During dietary deficiency of linoleate or α-lino-lenate, oleate can also be desaturated and chain elon-gated to the PUFA eicosatrienoate (20:3n-9). Hence, most but not all PUFAs are derived from linoleate or α-linolenate.

Figure 6.13 Conversion of linoleic (18:2n-6) and α-linolenic (18:3n-3) acids to their respective longer chain, more unsaturated polyunsaturates. In mem-branes, linoleic and arachidonic acids are the prin-cipal n-6 polyunsaturates, while docosahexaenoic acid is the principal n-3 polyunsaturate. Hence, these two families of fatty acids have different affinities for the desaturation and chain-elongation enzymes. This pathway is principally based in the endoplasmic reticulum but appears to depend on peroxisomes for the final chain shortening, which involves 24 carbon intermediates that are not illustrated.

Chain elongation of saturated and unsaturated fatty acids occurs primarily in the endoplasmic retic-ulum, although it has also been demonstrated to occur in mitochondria. Unlike the desaturation steps immediately before and after, the elongation steps do not appear to be rate limiting in the metabolism of linoleate or α-linolenate.


Despite the capacity to insert at least three double bonds in both n-3 and n-6 polyunsaturates, there is no proof that a 4 desaturase exists to insert the final double bond in docosapentaenoate (22:5n-6) or doc-osahexaenoate (Figure 6.13). Rather, it appears that the precursors to these two fatty acids undergo a second elongation, repeated 6 desaturation followed by chain shortening in peroxisomes. This unexpect-edly convoluted series of steps is corroborated by the docosahexaenoate deficiency observed in disorders of peroxisomal biogenesis such as Zellweger’s syndrome.


Opposite to the desaturation process is hydrogena-tion or removal of unsaturated bonds in lipids. Rumen bacteria are the only organisms known to have this capability. As in chemical hydrogenation practiced by the food industry, biohydrogenation in the rumen can be incomplete, resulting in the formation of small amounts of trans isomers, particularly of oleate, lino-leate, and α-linolenate, which are found in milk fat.


Eicosanoids are 20-carbon, oxygen-substituted cyclized metabolites of dihomo-γ-linolenate, arachi-donate, or eicosapentaenoate. They are produced via a cascade of steps starting with the cyclooxygenase or lipoxygenase enzymes present in microsomes. The main cyclooxygenase products comprise the classical prostaglandins, prostacyclin and the thromboxanes. The main lipoxygenase products are the leukotrienes (slow-reacting substances of anaphylaxis) and the noncyclized hydroperoxy derivatives of arachidonate that give rise to the hepoxylins and lipoxins (Figure 6.14).

 Eicosanoids are considered to be fast-acting local hormones, the presence of which in the plasma and urine is largely a spillover from localized production,

Figure 6.14 The arachidonic acid cascade is a fundamental component of cell signal-ing during injury. Phospholipase A2 is immediately activated and the free arachi-donic acid thus released is accessible to a controlled peroxidation process involving several cyclooxygenases (constitutive or inducible) and lipoxygenases. Over 50 metabolically active products are poten-tially produced, depending on the tissue involved, the type of cell that has been stimulated, and the type of injury. Only the main classes of these metabolites are shown. Before excretion, they are further metabolized to stable products that are not shown. Several of the cyclooxygenase products are competitive with each other, such as the platelet-aggregating and blood vessel wall-constricting effects of thromboxane A2 (TXA2) produced in plate-lets, versus the opposite effects of prosta-cyclin (PGI2) derived from the blood vessel wall. HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; PG, prostaglandin; TX, thromboxane.

usually in response to an injury or a stimulus that releases the free precursor, most commonly arachido-nate. The site of highest eicosanoid concentration appears to be the seminal fluid, although some species have no detectable eicosanoids in semen. Eicosanoids are second messengers modulating, among other pathways, protein phosphorylation. The lung is a major site of eicosanoid inactivation.


Four important characteristics of eicosanoid action should be noted. First, individual eicosanoids often have biphasic actions as one moves from very low through to higher, often pharmacological, concentra-tions. Thus, effects can vary dramatically depending not only on the experimental system but also on the eicosanoid concentration used. Second, several of the more abundant eicosanoids arising from the same precursor fatty acid have opposite actions to each other. For instance, prostacyclin and thromboxane A2 are both derived from arachidonate but the former originates primarily from the endothelium and inhibits platelet aggregation, while the latter orig-inates primarily from platelets and is a potent plate-let-aggregating agent. Third, competing eicosanoids derived from dihomo-γ-linolenate (1 series) and from eicosapentaenoate (3 series) often have effects that oppose those derived from arachidonate (2 series) (Figures 6.14 and 6.15). Thus, unlike prostaglandin E2, prostaglandin E1 has anti-inflammatory actions, reduces vascular tone, and inhibits platelet aggrega-tion. Fourth, varying the ratio of the precursor fatty acids in the diet is an effective way to modify eico-sanoid production. Thus, eicosapentaenoate and dihomo-γ-linolenate inhibit the synthesis of 2 series eicosanoids derived from arachidonate. This occurs by inhibiting arachidonate release from membranes by phospholipase A2 and its cascade through the cyclooxygenases and lipoxygenases. The overproduc-tion of 2 series eicosanoids is associated with higher blood pressure, increased platelet aggregation, and inflammatory processes, and can be effectively inhib-ited by dietary approaches using oils rich in eicosap-entaenoate and γ-linolenate (18:3n-6), the precursor to dihomo-γ-linolenate.


Stable analogues of some classical prostaglandins have specialized medical applications, including the termination of pregnancy and the closing of a patent

Figure 6.15 Arachidonic acid is not the only 20-carbon polyunsaturated fatty acid that can be metabolized via the cyclooxygenases and lipoxygen-ases; both dihomo-γ-linolenic acid (20:3n-6) and eicosapentaenoic acid (20:5n-3) are well-established precur-sors as well, and produce prostaglan-dins (PGs) and leukotrienes (LTs) that are frequently competitive with those produced from arachidonate, thereby neutralizing the effects of the arachido-nate cascade (see Figure 6.14). This provides a critical balance in the overall reaction to cell injury.

ductus arteriosus shortly after birth. Many anti-inflam-matory and anti-pyretic drugs are inhibitors of eico-sanoid synthesis. One potentially dangerous side-effect of inhibiting eicosanoid synthesis is gastric erosion and bleeding. Receptor antagonists of leukotrienes are effective in reducing the symptoms of asthma.

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