Very-long-chain fatty acids metabolism

Cartier, N., J. Lopez, P. MouUier, F. Rocchiccioli, M. O. Rolland, P. Jorge, J. Mosser, J. L. Mandel, P. F. Bougneres, O. Danos, ruid et al. 1995. Retroviral-mediated gene transfer corrects very-long-chain fatty acid metabolism in adrenoleukodystrophy fibroblasts. Proc Natl Acad Sci 92 1674-1678. 

Fatty acid transport proteins (FATPs) are an evolutionary conserved family of integral membrane proteins found at the plasma membrane and on internal membranes. FATPs facilitate the unidirectional uptake and/ or intracellular activation of unesterified long-chain and very long-chain fatty acids (LCFAs) into a variety of lipid-metabolizing cells and tissues. 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

In mitochondria, there are four fatty acyl CoA dehydrogenase species, each of which has a specificity for either short-, mediurr-long-, or very-long-chain fatty acids. MCAD deficiency, an autos mal, recessive disorder, is one of the most common inborn errors of metabolism, and the most common inborn error of fatty add oxidation, being found in 1 in 12,000 births in the west, and 1 in 40,000 worldwide. It causes a decrease in fatty acid oxidation and severe hypoglycemia (because the tissues cannot obtain full ener getic benefit from fatty acids and, therefore, must now rely on glu cose). Treatment includes a carbohydrate-rich diet. [Note Infants are particularly affected by MCAD deficiency, because they rely for their nourishment on milk, which contains primarily MCADs. 

Figure 13-2. The metabolic pathway for the metabolism of very long chain fatty acids (VLCFA) in the peroxisome.

Very long chain fatty acids are initially oxidized in the peroxisome where the initial oxidation step is catalyzed by acyl-CoA oxidase and the subsequent steps in fS-oxidation are catalyzed by a multi-enzyme complex with hydratase, dehydo-genase, and thiolase activities. Unsaturated fatty acids require additional enzymatic activities, including enoyl-CoA isomerase and dienoyl-CoA reductase. Readers are directed to Vance and Vance (2) for additional details regarding fi-oxidation, including the details of the metabolic reactions. 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

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.

Gassagne, G Bessoule, J-J Schneider, F Lessire, R Sturbois, B Moreau, P Spinner, G. Modulation of the very-long-chain fatty acid (VLGFA) formation in leek. In Kader J-K, Mazliak P, editors. Plant Lipid Metabolism. Dordrecht Kluwer, 1995, 111-114. 

Moreau P., Lessire R. and Casagne C. (1984) - In vivo membrane transfer of very long chain fatty acids synthesized by etiolated leek seedlings in Structure Function and Metabolism of plant Lipids, Siegenthaler P.A. et Eichenberger W., eds, Elsevier, Amsterdam, p. 307-310. 

Figure 10-5. Intrahepatic metabolism of free fatty acids (FFA). CPT I, CPT II, carnitine palmitoyltransferase I, II, respectively LCFA, long-chain fatty acid VLDL, very low-density lipoprotein. 1, Long-chain acyl-CoA synthase 2, acetoacetyl-CoA thiolase 3, hydrox-ymethylglutaryl-CoA synthase 4, hydroxymethylglutaryl-CoA lyase 5, 3-hydroxybutyrate dehydrogenase 6, acetyl-CoA carboxylase 7, fatty acid synthase 8, glycerolphosphate acyltransferase Reprinted with permission from Girard et al. (1992).

The route of metabolism for a fatty acid depends somewhat on its chain length. Fatty acids are generally classified as very-long-chain length fatty acids (greater than C20), long-chain fatty acids (C12-C20), medium-chain fatty acids (C6-C12), and short-chain fatty acids (C4). 

Albumin is a protein polypeptide. Albumin has a molecular weight of 66.5 kDa and is the most abundant plasma protein, which is present in the concentration of 35-50 g/L in human serum and is synthesized in the liver. Human serum albumin (HSA) has a half-life of 19 days. It acts as a solubilizing agent for long chain fatty acids and is therefore essential for the transport and metabolism of lipids. It binds very well to penicillins, sulfonamides, indole compounds, benzodiazepines, copper, and nickel in a specific and calcium and zinc in a relatively nonspecific manner. It is responsible for osmotic pressure of the blood. 

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