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
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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.
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DOI: 10.1124/jpet.103.064717.
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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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