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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 7, 2006; DOI: 10.1124/jpet.106.108175

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Received for publication May 23, 2006.
Revised July 5, 2006.
Accepted for publication July 6, 2006.

The Role of Retinoid X Receptor alpha (RXR{alpha}) in Regulating Alcohol Metabolism

Maxwell A. Gyamfi 1, Michael George Kocsis 1, Lin He 1, Guoli Dai 1, Alphonse J Mendy 1, Yu-Jui Yvonne Wan 1*

1 University of Kansas Medical Center

* Address correspondence to: E-mail: ywan{at}kumc.edu

Abstract

There is substantial overlap in retinol and alcohol metabolism. Mice, which lack the retinoic acid (RA) receptor-retinoid X receptor {alpha} (RXR{alpha}) expression in the liver, are more susceptible to alcoholic liver disease. To investigate the interaction between RXR{alpha} and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXR{alpha}-deficient (RXR{alpha} KO) mice. Hepatocyte RXR{alpha} deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome associated Adh1 mRNA were present in the mutant mouse livers suggesting increased ADH1 protein synthesis in the RXR{alpha} KO compared to the wild type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXR{alpha} deficiency. While ethanol clearance was increased, acetaldehyde elimination was reduced when RXR{alpha} was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase 2 (ALDH2) and cytosolic ALDH activities were reduced in the mutant mice compared to the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semi-quantitative RT-PCR indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXR{alpha} expression. Thus, RXR{alpha} differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXR{alpha} KO than wild type mice. Our results reveal the central role of RXR{alpha} in ethanol metabolism.


Key words: Alcohol Dehydrogenase, Alcoholic Liver Disease, Aldehyde Dehydrogenase, Cytochrome P450 2E1, Glutathione S-transferase, Retinoid X Receptor alpha


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M. A. Gyamfi, L. He, S. W. French, I. Damjanov, and Y.-J. Y. Wan
Hepatocyte Retinoid X Receptor {alpha}-Dependent Regulation of Lipid Homeostasis and Inflammatory Cytokine Expression Contributes to Alcohol-Induced Liver Injury
J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 443 - 453.
[Abstract] [Full Text] [PDF]


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