Peroxisome proliferator-activated receptor α (PPARα) agonist treatment reverses PPARα dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice

Monika Fischer, Min You, Michinaga Matsumoto, David W. Crabb

Research output: Contribution to journalArticle

203 Scopus citations

Abstract

Proper function of the peroxisome proliferator-activated receptor α (PPARα) is essential for the regulation of hepatic fatty acid metabolism. Fatty acid levels are increased in liver during the metabolism of ethanol and should activate PPARα. However, recent in vitro data showed that ethanol metabolism inhibited the function of PPARα. We now report that ethanol feeding impairs fatty acid catabolism in the liver in part via blocking PPARα-mediated responses in C57BL/6J mice. Ethanol feeding decreased PPARα/retinoid X receptor α binding in electrophoretic mobility shift assay of liver nuclear extracts. mRNAs for PPAR-regulated genes were reduced (long chain and medium chain acyl-CoA dehydrogenases) or failed to be induced (acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase, very long chain acyl-CoA synthetase, very long chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals, and ethanol feeding did not increase the rate of fatty acid β-oxidation. Wy14,643, a PPARα agonist, restored the DNA binding activity of PPARα/retinoid X receptor α, induced mRNA levels of PPARα target genes, stimulated the rate of fatty acid β-oxidation, and prevented fatty liver in ethanol-fed animals. Impairment of PPARα function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by Wy14,643.

Original languageEnglish (US)
Pages (from-to)27997-28004
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number30
DOIs
StatePublished - Jul 25 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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