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J. Biol. Chem., Vol. 279, Issue 27, 28113-28121, July 2, 2004

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Post-transcriptional Regulation of Sterol Regulatory Element-binding Protein-1 by Ethanol Induces Class I Alcohol Dehydrogenase in Rat Liver^*

Ling He, Frank A. Simmen, Martin J. J. Ronis¶, and Thomas M. Badger¶||

From the Arkansas Children's Nutrition Center and the Departments of Physiology and Biophysics and ^¶Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202

Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids. Continuous intragastric infusion of ethanol-containing diets as part of total enteral nutrition generates well defined 6-day cycles (pulses) of urine ethanol concentrations (UECs) in rats. Pulsatile UECs are the result of cyclical expression and activity of the principal alcohol-metabolizing enzyme, hepatic Class I alcohol dehydrogenase (ADH), and this mechanism involves regulated CCAAT/enhancer-binding protein- expression and binding to the ADH promoter. In this study, we further explore the molecular mechanism for ethanol-induced ADH expression during the UEC pulse in adult male rats fed ethanol by total enteral nutrition for 21–30 days. In hypophysectomized rats, in which the ADH protein increased by 6-fold, the nuclear form of SREBP-1 decreased by 7-fold. Because the ADH promoter contains two canonical sterol response element (SRE) sites (–63 to –53 and –52 to –40 relative to the transcription start site), electrophoretic mobility shift assays were conducted using an ADH-specific SRE site. Hepatic nuclear protein binding decreased by 2.4-fold on the ascending limbs and by 3.6-fold on the descending limbs of UEC pulses (p < 0.05). The specificity of nuclear protein binding to the ADH-SRE site was confirmed using antibody and UV cross-link assays. The in vivo binding status of SREBP-1 to ADH-SRE sites, as measured by the chromatin immunoprecipitation assay, had a pattern very similar to the electrophoretic mobility shift assay results. Functional analysis of the ADH-SREs demonstrated these sites to be essential for ADH transcription. In vitro transcription assays demonstrated that depletion of the SREBP-1 protein from nuclear extracts increased transcription activity by 5-fold and that the liver X receptor agonist T0901317 (a known activator of SREBP-1c transcription) reduced in vitro expression of ADH mRNA by 2-fold. We conclude that SREBP-1 is a negative regulator of the ADH gene and may work in concert with the CCAAT/enhancer-binding proteins to mediate ethanol induction of ADH in vivo.

Received for publication, January 28, 2004 , and in revised form, April 22, 2004.

^* 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: Arkansas Children's Nutrition Center, 1120 Marshall St., Little Rock, AR 72202. Tel.: 501-364-2781; Fax: 501-364-2818; E-mail: badgerthomasm{at}uams.edu.

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