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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #165883
Title: POST-TRANSCRIPTIONAL REGULATIONS OF STEROL REGULATORY ELEMENT-BINDING PROTEIN-1 BY ETHANOL INDUCES CLASS I ALCOHOL DEHYDROGENASE IN RAT LIVER

Author
item HE, LING - UAMS
item SIMMEN, FRANK - UAMS
item RONIS, MARTIN - UAMS
item BADGER, THOMAS - UAMS

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2004
Publication Date: 4/28/2004
Citation: He, L., Simmen, F.A., Ronis, M.J., Badger, T.M. 2004. Post-transcriptional regulations of sterol regulatory element-binding protein-1 by ethanol induces class I alcohol dehydrogenase in rat liver. Journal of Biological Chemistry.279(27):28113-28121.

Interpretive Summary: The ACNC is interested in how dietary factors, including alcohol, affect metabolism. One metabolic area of importance relates to insulin, insulin resistance and obesity. We have found that alcohol regulates it's own metabolism, partly through insulin signaling. The protein family, SREBP-1, is involved in insulin regulation of several cellular functions and the current study demonstrated that alcohol depletes this protein. We think this is related to insulin resistance. This may have implications for obesity and the insulin resistance that develops during obesity. Future studies will explore this in detail.

Technical Abstract: Members of the 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 (TEN) 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 mechanism involves regulated C/EBPß expression and binding to the ADH promoter. In the present study, we further explore the molecular mechanism for ethanol-induced ADH expression during the UEC pulse in adult male rats fed ethanol by TEN for 21-30 days. In hypophysectomized rats, where the ADH protein increased ~6-fold, the nuclear form of SREBP-1 decreased ~7-fold. The ADH promoter region contains two canonical SRE sites and hepatic nuclear protein binding (EMSA) decreased 2.4-fold at ascending and 3.6-fold at descending limbs of UECs (P<0.05). The specificity of nuclear protein binding to the ADH-SREs site was confirmed by using antibody and UV cross-link assays. In vivo binding status of SREBP-1 protein to ADH-SRE sites, as measured by the chromatin immunoprecipitation assay, had a pattern very similar to the EMSA results. Functional analysis of ADH-SREs demonstrated these sites to be essential for ADH transcription. In vitro transcription assays demonstrated that depletion of SREBP-1 protein from nuclear extracts increased transcription activity ~5-fold. We conclude that SREBP-1 is a negative regulator of the ADH gene that may work in concert with C/EBPs to mediate ethanol induction of ADH in vivo.