Alcoholic Liver Injury in the Rat Is Associated with Reduced Expression of Peroxisome Proliferator-alpha (PPARalpha)-Regulated Genes and Is Ameliorated by PPARalpha Activation

摘要

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-acti-vated receptor-alpha (PPARalpha),and peroxisomal fatty acyl CoA oxidase (FACO).Four groups of rats (n=5) were fed intragas-trically,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.PPARalpha mRNA levels were not different between groups,although there was a trend toward increased levels in ethanol-fed rats.We calculated L-FABP/PPARalpha and FACO/PPARalpha ratios as a measure of FACO and L-FABP up-regulation relative to PPARalpha expression.Both FACO/PPARalpha and L-FABP/PPARalpha ratios were significantly decreased in FE rats.However,only L-FABP/PPARalpha 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 PPARa response genes was impaired in ethanol-fed rats,we determined whether activation of PPARalpha would normalize the PPARalpha response and prevent the pathological changes in ethanol-fed rats.Treatment with clofibrate,a PPARalpha-activating ligand,led to a marked decrease in fatty liver and complete abrogation of necroinflammatory changes in FE rats.Also,nuclear factor kappaB activation and up-regulation of tumor necrosis factor-a and cyclooxygenase-2 was also abolished in clofi-brate-treated rats.We conclude that adaptive gene regulation of FACO and L-FABP by PPARalpha is impaired in ethanol-fed rats and that treatment with clofibrate,a PPARalpha ligand,prevents alcohol-induced pathological liver injury,possibly by reversing the above changes.