Fatty acid metabolism desaturation

Figure 2 Essential fatty acid metabolism desaturation and elongation of n-6 and n-3.

The EFA metabolism is presented in several extensive reviews.9 16 17 Much of the information concerning EFA physiology and biochemistry has been derived from work in hepatocytes and may be of limited relevance to epidermis since a major role of the liver is to convert dietary lipids into energy stores. Meanwhile, keratinocytes are involved in the fatty acid metabolism required both for normal cellular processes and the specialized role in the permeability barrier. Unlike the liver, the epidermis does not possess the capacity to desaturate at the A5 or A6 position, and therefore the skin relies on a supply of AA, LA, and ALA from the bloodstream. There is evidence for a distinct fatty acid binding protein in keratinocyte plasma membranes that is involved in EFA uptake into the skin and also recycling of free fatty acids from the stratum corneum.18 The transport mechanism in epidermis differs from that in hepatocytes since there is preferential uptake of LA over OA, which may function to ensure adequate capture of LA for barrier lipid synthesis.18... 

Fatty acid desaturases are responsible for catalysis of the O2- and NADH-dependent desaturation reactions, the insertion of a cis double bond in saturated fatty acids (Table 1) [144]. Such reactions are important in fatty acid metabolism and processes that facilitate the delivery of lipid precursors to prostaglandins and cell membranes [347]. Both soluble and membrane-bound desaturases exist, which exhibit different substrate specificities and reactivities [144,348]. The soluble stearoyl-acyl carrier protein desaturase from Ricinus communis (castor seeds) is the best characterized desaturase and catalyzes the insertion of a cis double bond between the C-9 and C-10 carbon atoms of stearoyl ACP to yield an important in... 

Particularly in the metabolism of the polyunsaturated fatty acids, the process of elongation occurs in sequence with desaturation to produce the specific acids required by the tissues in the body. 

Several studies have evaluated the effects of oral di(2-ethylhexyl) adipate on various aspects of hepatic lipid metabolism. Feeding di(2-ethylhexyl) adipate (2% of diet) to male Wistar rats for seven days resulted in increased hepatic fatty acid-binding protein as well as in increased microsomal stearoyl-CoA desaturation activity (Kawashima et al., 1983a,b). Feeding the compound at this dose for 14 days resulted in increased levels of hepatic phospholipids and a decline in phosphatidyl-choline phosphatidylethanolamine ratio (Yanagita et al., 1987). Feeding di(2-ethyl-hexyl) adipate (2% of diet) to male NZB mice for five days resulted in induction of fatty acid translocase, fatty acid transporter protein and fatty acid binding protein in the liver (Motojima et al., 1998). 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

The possibility that the second electron is derived from NADH through cytochrome bs has been the subject of argument for some time and has yet to be completely resolved. Cytochrome bs is a widely distributed microsomal heme protein that is involved in metabolic reactions such as fatty acid desaturation that involve endogenous substrates. It is clear, however, that cytochrome bs is not essential for all... 

Palmitic acid may be converted to stearic acid (C1K 0) by elongation of the carbon chain. Desaturation of stearic acid produces oleic acid (C18 1 A9). Linoleic acid (Ci8 2A9,12), however, cannot be synthesized in mammalian tissues. Therefore, it is an essential fatty acid for animals and must be obtained from the diet it has two important metabolic roles. One is to maintain the fluid state of membrane lipids, lipoproteins, and storage lipids. The other role is as a precursor of arachidonic acid, which has a specialized role in the formation of prostaglandins (Sec. 13.9). 

Fatty Acids Synthesis, Elongation, and Desaturation. The main objective of feeding fats to animals is to provide a concentrated energy source, not to have the fat stored in the tissues. Recognized EFA requirements are no more than several percent of dry matter at the most, but the critical roles they play in maintaining the metabolic machinery has attracted the majority of current research on dietary fat utilization. 

Experiences in cat nutrition underscore the fallacy of assuming that metabolic pathways found in one species are automatically present in others. Early studies on metabolism of PUFA were conducted on rats, which have high A6 and A5 desa-turase abilities to convert linoleic acid (18 2n-6) to the prostaglandin precursors dihomo-y-linolenic acid (20 3 -6) and arachidonic acid (20 4 -6), respectively. This led to the assumption that other species can desaturate polyunsaturated fatty acids equally well. Over a period of time, it was shown that cats are not able to convert 18 2 -6 to 20 3n-6 or 20 4 -6. The NRC currently recommends the inclusion of 5 g linoleic acid and 0.2 g arachidonic acid/kg diet dry matter. 

Fig. (4). Metabolic pathway of essential fatty acids of the n-6 and n-3 series via elongation-desaturation steps.

Fig. 1. Metabolic pathway of essential fatty acids. Recent evidence indicated that 22 6n-3 are produced by [l-oxidation of 24 6n-3, which is desaturated from 24 5n-3, after elongation from 22 5n-3. Very long-chain fatty acids in the box are found in the retina however, the metabolism and function is not known.

Once ingested, these essential fatty acids can be metabolized into longer, more unsaturated products (Holman, 1968). This process involves sequential desaturation (adding double bonds) and chain elongation (adding carbon atoms), as shown in Fig. 1. The important aspect of Fig. 1 is that the n-6 and n-3 families compete for the enzymes responsible for desaturation (Sinclair, 1993). The main metabolite of the n-6 series is arachidonic acid (20 4n-6, AA), whereas eicosapentaenoic acid (20 5n-3, EPA) and docosahexaenoic acid (22 6n-3, DHA) are the main metabolites ofthe n-3 series (Holman, 1968). The metabolic pathways leading to DHA are complicated by involving retroconversion from 24 6n-3 to 22 6n-3 (DHA) (Voss et al., 1991). 

The metabolic pathways for synthesis of n-6 and n-3 families of polyunsaturated fatty acids from the essential fatty acids, linoleic acid (LA) (18 2 [n-6]) and a-linolenic acid (18 3 [n-3]), respectively, are showninFig. 2. Conversion of LA to arachidonic acid (AA) occurs via A6 desaturation to yield y-linolenic acid (GLA), then an elongation step to produce dihomo-y-linolenic acid (DHGL A) and A5 desaturation, to form AA. The A6 and A5 microsomal desaturases have been reported to utilize both NADH and NADPH as cofactors in vitro (Brenner 1977). Whether there is a more stringent pyridine nucleotide requirement in vivo is not known with certainty. Desaturase activities are especially abundant in the liver. 

Linoleic acid (LA or 18 2n-6) An 18-carbon, two double-bond fatty acid. It is the most predominant PUFA in the Western diet. It is found in mayoimaise, salad dressings, and in the seeds and oils of most plants, with the exception of coconut, cocoa, and palm. Linoleic acid is metabolized into longer-chain fatty acids, such as arachidonic acid and gamma-linolenic acid, in animals through a process of chain elongation and desaturations. 

---