Nonalcoholic Steatosis and Steatohepatitis III. Peroxisomal b-oxidation, PPARa, and steatohepatitis

Reddy, Janardan K. Nonalcoholic Steatosis and Steatohepatitis. III. Peroxisomal b-oxidation, PPARa, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol 281: G1333–G1339, 2001.—Peroxisomes are involved in the b-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 H2O2. There are two complete sets of b-oxidation enzymes present in peroxisomes, with each set consisting of three distinct enzymes. The classic PPARaregulated and inducible set participates in the b-oxidation of straight-chain fatty acids, whereas the second noninducible set acts on branched-chain fatty acids. Long-chain and verylong-chain fatty acids are also metabolized by the cytochrome P-450 CYP4A v-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal b-oxidation. Evidence derived from mouse models of PPARa and peroxisomal b-oxidation deficiency highlights the critical importance of the defects in PPARa-inducible b-oxidation in energy metabolism and in the development of steatohepatitis.