Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis.

摘要

Peroxisomes are involved in the beta-oxidation chain shortening of long-chain and very-long-chain fatty acyl-CoAs, long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates, and in the process, they generate H(2)O(2). There are two complete sets of beta-oxidation enzymes present in peroxisomes, with each set consisting of three distinct enzymes. The classic PPAR alpha-regulated and inducible set participates in the beta-oxidation of straight-chain fatty acids, whereas the second noninducible set acts on branched-chain fatty acids. Long-chain and very-long-chain fatty acids are also metabolized by the cytochrome P-450 CYP4A omega-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal beta-oxidation. Evidence derived from mouse models of PPAR alpha and peroxisomal beta-oxidation deficiency highlights the critical importance of the defects in PPAR alpha-inducible beta-oxidation in energy metabolism and in the development of steatohepatitis.