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TOXICOLOGY

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

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (A.A.N.); Department of Medicine, Weill Medical College of Cornell University and Nutrition Center at Strang Cancer Prevention Center, New York, New York (A.J.D.); Research Unit of Alcohol Diseases, Helsinki University Central Hospital, Helsinki, Finland (K.J.); and Department of Medicine, University of California, San Francisco, California (N.M.B.)

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

Address correspondence to: Dr. Amin A. Nanji, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce Street, Founders 7.103, Philadelphia, PA 19104-4283. E-mail: amin.nanji{at}uphs.upenn.edu

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