Nonalcoholic steatosis and steatohepatitis III. Peroxisomal β-oxidation, PPARα, and steatohepatitis

Peroxisomes are involved in the β-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 β-oxidation enzymes present in peroxisomes, with each set consisting of three distinct enzymes. The classic PPARα regulated and inducible set participates in the β-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 ω-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal β-oxidation. Evidence derived from mouse models of PPARα and peroxisomal β-oxidation deficiency highlights the critical importance of the defects in PPARα-inducible β-oxidation in energy metabolism and in the development of steatohepatitis.