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Research ArticleTOXICOLOGY

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 J. Dannenberg, Kalle Jokelainen and Nathan M. Bass
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 417-424; DOI: https://doi.org/10.1124/jpet.103.064717
Amin A. Nanji
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Andrew J. Dannenberg
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Kalle Jokelainen
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Nathan M. Bass
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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. Ethanolfed 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.

Footnotes

  • This study was supported in part by a grant from the National Institute of Alcoholism and Alcohol Abuse (AA12893). K.J. was supported by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Yrjö Jahnsson Foundation.

  • DOI: 10.1124/jpet.103.064717.

  • ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; FACO, fatty acyl CoA oxidase; l-FABP, liver fatty acid binding protein; CD, corn oil plus dextrose; CE, corn oil plus ethanol; FD, fish oil-dextrose; FE, fish oil-ethanol; RT, reverse transcription; PCR, polymerase chain reaction; TBARS, thiobarbituric acid-reactive substances; NF-κB, nuclear factor κB; TNF, tumor necrosis factor; COX, cyclooxygenase.

    • Received December 19, 2003.
    • Accepted March 10, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleTOXICOLOGY

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 J. Dannenberg, Kalle Jokelainen and Nathan M. Bass
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 417-424; DOI: https://doi.org/10.1124/jpet.103.064717

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Research ArticleTOXICOLOGY

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 J. Dannenberg, Kalle Jokelainen and Nathan M. Bass
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 417-424; DOI: https://doi.org/10.1124/jpet.103.064717
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