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 four consecutive reactions to preferentially metabolize very long chain fatty acids. The first step of this system, catalyzed by acyl-CoA oxidase (AOX), converts fatty acyl-CoA to 2-trans-enoyl-CoA. Herein, we show that mice deficient in AOX exhibit steatohepatitis, increased hepatic H2O2 levels, and hepatocellular regeneration, leading to a complete reversal of fatty change by 6 to 8 months of age. The liver of AOX-/- mice with regenerated hepatocytes displays profound generalized spontaneous peroxisome proliferation and increased mRNA levels of genes that are regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). Hepatic adenomas and carcinomas develop in AOX-/- mice by 15 months of age due to sustained activation of PPARalpha. These observations implicate acyl-CoA and other putative substrates for AOX, as biological ligands for PPARalpha; thus, a normal AOX gene is indispensable for the physiological regulation of PPARalpha.
Fan
C Y
CY
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.
Pan
J
J
Usuda
N
N
Yeldandi
A V
AV
Rao
M S
MS
Reddy
J K
JK
D042962:Acyl-CoA Oxidase; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D008830:Microbodies / Q000201:enzymology*; D010088:Oxidoreductases / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase