Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-Coa oxidase: Implications for peroxisome proliferator-activated receptor α natural ligand metabolism

Chun Yang Fan, Jie Pan, Nobuteru Usuda, Anjana V. Yeldandi, M. Sambasiva Rao, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

287 Scopus citations

Abstract

Peroxisomal β-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 acylCoA 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 α (PPARα). Hepatic adenomas and carcinomas develop in AOX-/- mice by 15 months of age due to sustained activation of PPARα. These observations implicate acyl-CoA and other putative substrates for AOX, as biological ligands for PPARα; thus, a normal AOX gene is indispensable for the physiological regulation of PPARα.

Original languageEnglish (US)
Pages (from-to)15639-15645
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number25
DOIs
StatePublished - Jun 19 1998

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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