Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-α (PPARα)-regulated genes and is ameliorated by PPARα activation

Amin A. Nanji, Andrew Dannenberg, Kalle Jokelainen, Nathan M. Bass

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Alcoholic liver disease is associated with a state of hepatic fatty acid overload. We examined the effect of ethanol and different types of dietary fat on the expression of mRNA for liver fatty acid binding protein (L-FABP), peroxisome proliferator-activated receptor-α (PPARα), and peroxisomal fatty acyl CoA oxidase (FACO). Four groups of rats (n = 5) were fed intragastrically, a liquid diet with or without ethanol (10-16 g/kg/day) for 4 weeks. Pair-fed controls received isocaloric amounts of dextrose. The source of fat was either corn oil or fish oil. Ethanol-fed rats developed fatty liver, necrosis, and inflammation; the changes were more severe in the fish oil-ethanol (FE) rats. PPARα mRNA levels were not different between groups, although there was a trend toward increased levels in ethanol-fed rats. We calculated L-FABP/PPARα and FACO/PPARα ratios as a measure of FACO and L-FABP up-regulation relative to PPARα expression. Both FACO/PPARα and L-FABP/PPARα ratios were significantly decreased in FE rats. However, only L-FABP/PPARα was decreased in corn oil plus ethanol rats. Also, the level of L-FABP/mRNA correlated inversely with the degree of fatty liver in ethanol-fed rats. Since expression of PPARα response genes was impaired in ethanol-fed rats, we determined whether activation of PPARα would normalize the PPARα response and prevent the pathological changes in ethanol-fed rats. Treatment with clofibrate, a PPARα-activating ligand, led to a marked decrease in fatty liver and complete abrogation of necroinflammatory changes in FE rats. Also, nuclear factor κB activation and up-regulation of tumor necrosis factor-α and cyclooxygenase-2 was also abolished in clofibrate-treated rats. We conclude that adaptive gene regulation of FACO and L-FABP by PPARα is impaired in ethanol-fed rats and that treatment with clofibrate, a PPARα ligand, prevents alcohol-induced pathological liver injury, possibly by reversing the above changes.

Original languageEnglish (US)
Pages (from-to)417-424
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume310
Issue number1
DOIs
StatePublished - Jul 1 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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