Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor and peroxisomal fatty acyl-CoA oxidase: Genotype correlation with fatty liver phenotype

Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω- oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX(-/-) mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β- oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα(-/-) AOX(-/-) mice, suggests a role for PPARα- induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα(-/-) mice, a decrease in constitutive mitochondrial β- oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.