Absence of spontaneous peroxisome proliferation in enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase-deficient mouse liver: Further support for the role of fatty acyl CoA oxidase in PPARα ligand metabolism

Chao Qi, Yijun Zhu, Jie Pan, Nobuteru Usuda, Nobuyo Maeda, Anjana V. Yeldandi, M. Sambasiva Rao, Takashi Hashimoto, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Peroxisomes contain a classical L-hydroxy-specific peroxisome proliferator-inducible β-oxidation system and also a second noninducible D- hydroxy-specific β-oxidation system. We previously generated mice lacking fatty acyl-CoA oxidase (AOX), the first enzyme of the L-hydroxy-specific classical β-oxidation system; these AOX(-/-) mice exhibited sustained activation of peroxisome proliferator-activated receptor α (PPARα), resulting in profound spontaneous peroxisome proliferation in liver cells. These observations implied that AOX is responsible for the metabolic degradation of PPARα ligands. In this study, the function of enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (L-PBE), the second enzyme of this peroxisomal β-oxidation system, was investigated by disrupting its gene. Mutant mice (L-PBE(-/-)) were viable and fertile and exhibited no detectable gross phenotypic defects. L-PBE(-/-) mice showed no hepatic steatosis and manifested no spontaneous peroxisome proliferation, unlike that encountered in livers of mice deficient in AOX. These results indicate that disruption of classical peroxisomal fatty acid β-oxidation system distal to AOX step does not interfere with the inactivation of endogenous ligands of PPARα, further confirming that the AOX gene is indispensable for the physiological regulation of this receptor. The absence of appreciable changes in lipid metabolism also indicates that enoyl-CoAs, generated in the classical system in L-PBE(-/-) mice are diverted to D-hydroxy-specific system for metabolism by D-PBE. When challenged with a peroxisome proliferator, L- PBE(-/-) mice showed increases in the levels of hepatic mRNAs and proteins that are regulated by PPARα except for appreciable blunting of peroxisome proliferative response as compared with that observed in hepatocytes of wild type mice similarly treated. This blunting of peroxisome proliferative response is attributed to the absence of L-PBE protein in L-PBE(-/-) mouse liver, because all other proteins are induced essentially to the same extent in both wild type and L-PBE(-/-) mice.

Original languageEnglish (US)
Pages (from-to)15775-15780
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number22
DOIs
StatePublished - May 28 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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