Molecular mechanisms of alcoholic fatty liver: Role of peroxisome proliferator-activated receptor alpha

David W. Crabb, Andrea Galli, Monika Fischer, Min You

Research output: Contribution to journalArticle

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Abstract

Normal function of the peroxisome proliferator-activated receptor alpha (PPARα) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARα, and when fatty acid levels increase, activation of PPARα induces a battery of fatty acid-metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARα to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARα-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRα) as well as the ability of PPARα/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of mRNAs for several PPARα-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase I, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARα agonist, in the diet restored the DNA-binding activity of PPARα/RXR, induced mRNA levels of several PPARα target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade 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)35-38
Number of pages4
JournalAlcohol
Volume34
Issue number1
DOIs
StatePublished - Aug 1 2004

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Keywords

  • Beta-oxidation
  • Fatty liver
  • Nuclear receptor
  • Peroxisome proliferator

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Behavioral Neuroscience
  • Neuroscience(all)
  • Toxicology
  • Health(social science)

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