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J. Biol. Chem., Vol. 278, Issue 30, 27997-28004, July 25, 2003
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(PPAR) Agonist Treatment Reverses PPAR Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice*
From the Departments of Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine and Richard Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana 46202
Proper function of the peroxisome proliferator-activated receptor 
(PPAR) is essential for the regulation of hepatic fatty acid
metabolism. Fatty acid levels are increased in liver during the metabolism of
ethanol and should activate PPAR. However, recent in vitro
data showed that ethanol metabolism inhibited the function of PPAR. We
now report that ethanol feeding impairs fatty acid catabolism in the liver in
part via blocking PPAR-mediated responses in C57BL/6J mice. Ethanol
feeding decreased PPAR/retinoid X receptor binding in
electrophoretic mobility shift assay of liver nuclear extracts. mRNAs for
PPAR-regulated genes were reduced (long chain and medium chain acyl-CoA
dehydrogenases) or failed to be induced (acyl-CoA oxidase, liver carnitine
palmitoyl-CoA transferase, very long chain acyl-CoA synthetase, very long
chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals, and
ethanol feeding did not increase the rate of fatty acid 
-oxidation.
Wy14,643, a PPAR agonist, restored the DNA binding activity of
PPAR/retinoid X receptor , induced mRNA levels of PPAR
target genes, stimulated the rate of fatty acid -oxidation, and
prevented fatty liver in ethanol-fed animals. Impairment of PPAR
function during ethanol consumption contributes to the development of
alcoholic fatty liver, which can be overcome by Wy14,643.
Received for publication, February 28, 2003 , and in revised form, April 24, 2003.
* This work was supported in part by NIAAA, National Institutes of Health Grant AA06463 (to D. W. C.) and by Alcohol Research Center Grant P50 AA07611. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Indiana University School of
Medicine, 545 Barnhill Dr., Emerson Hall 317, Indianapolis, IN 46202-5124.
Tel.: 317-274-8438; Fax: 317-274-1437; E-mail:
dcrabb{at}iupui.edu.
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