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| Role of peroxisomes in fatty acid oxidation |
| Peroxisomes are subcellular organelles found in all nucleated cells. They are the principal sites of production of hydrogen peroxide (H2O2) in the cell, and account for nearly 20% of oxygen consumption in hepatocytes. They are able to conduct β-oxidation of long and very-long-chain fatty acids by a pathway similar to mitochondrial oxidation, but with some significant differences, e.g. the oxidation of acyl-CoAs is catalyzed by an oxidase, producing H2O2, rather than FADH2. Peroxisomes are relatively inefficient at catabolism of short-chain fatty acids, so products such as hexanoyl- and octanoylcarnitine are exported, to be catabolized in the mitochondrion. Peroxisomes are also the primary site of oxidation of branched-chain fatty acids and medium-chain α,ω-dicarboxylic acids produced by microsomal or peroxisomal ω-oxidation of fatty acids. The fibrates are a class of hypolipidemic drugs that act by inducing peroxisomal proliferation in liver. |
| Peroxisomes are believed to have a role in production of acetyl-CoA for anabolic reactions, e.g. the biosynthesis of cholesterol and polyisoprenoids (Chapter 16). Peroxisomes also have a special role in the metabolism of very-long-chain fatty acids and phytanic acids (see below). Zellweger syndrome, resulting from the absence of peroxisomes, is characterized by accumulation of long-chain fatty acids and branched chain, pristanic acids in plasma and tissues. |
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| CoA is a large, polar nucleotide derivative, and cannot penetrate the mitochondrial inner membrane. Thus, for the transport of long-chain fatty acids, the fatty acid is first transferred to the small molecule, carnitine, by carnitine palmitoyl transferase-I (CPT-I), located in the outer
mitochondrial membrane. An acyl-carnitine transporter or translocase in the inner mitochondrial membrane then mediates transfer of the fatty acid into the mitochondrion, where CPT-II regenerates the acyl-CoA, releasing free carnitine. The carnitine shuttle (Fig. 14.2) operates by an antiport mechanism in which free carnitine and the acyl-carnitine derivative move in opposite directions across the inner mitochondrial membrane. The shuttle is an important site in the regulation of fatty acid oxidation. As discussed in the next chapter, the carnitine shuttle is inhibited by malonyl-CoA after the ingestion of carbohydrate-rich meals. Malonyl-CoA prevents the futile cycle in which newly synthesized fatty acids would be oxidized in the mitochondrion and promotes their export from the liver for storage in adipose tissue.
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