STEATOHEPATITIS, SPONTANEOUS PEROXISOME PROLIFERATION AND LIVER-TUMORS IN MICE LACKING PEROXISOMAL FATTY ACYL-COA OXIDASE - IMPLICATIONS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA NATURAL LIGAND METABOLISM

Peroxisomal beta-oxidation system consists of fc,ur consecutive reacti ons to preferentially metabolize very long chain fatty acids. The firs t step of this system, catalyzed by acyl-CoA oxidase (AOX), converts f atty acyl-CoA to 2-trans-enoyl-CoA. Herein, we show that mice deficien t in AOX exhibit steatohepatitis, increased hepatic H2O2 levels, and h epatocellular regeneration, leading to a complete reversal of fatty ch ange by 6 to 8 months of age. The liver of AOX-/- mice with regenerate d hepatocytes displays profound generalized spontaneous peroxisome pro liferation and increased mRNA levels of genes that are regulated by pe roxisome proliferator-activated receptor alpha (PPAR alpha). Hepatic a denomas and carcinomas develop in AOX-/- mice by 15 months of age due to sustained activation of PPAR alpha. These observations implicate ac yl-CoA and other putative substrates for AOX, as biological ligands fo r PPAR alpha; thus, a normal AOX gene is indispensable for the physiol ogical regulation of PPAR alpha.