Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 10/3/2004
Publication Date: 3/15/2005
Citation: Badger, T.M., He, L., Simmen, F.A., Ronis, M.J. 2005. Ethanol induces rat hepatic alcohol dehydrogenase (ADH) class i by interfering with post-translational regulation of sterol regulatory element binding protein-1 (SREBP-1). The Toxicologist. 84(S-1):392. Interpretive Summary: Alcohol represents a significant percentage of the total caloric intake of large portion of American adult diets. In addition to its caloric content, alcohol has many biological effects that are important for health; some beneficial effects and some adverse effects. Alcohol is metabolized by an enzyme, ADH, which is important in fatty acid and sterol metabolism and bile acid formation. We have been studying the effects of alcohol on metabolism on ADH and on a factor known as SREBP. SREBP is an important factor through which insulin signals the cell to perform certain tasks. It turns out that alcohol decreases SREBP which results in elevates ADH action and subsequently increases alcohol metabolism. The net result is that alcohol can regulate its own metabolism by inhibiting production of SREBP. This has important implications in obesity and diabetes, since SREBPs are important in insulin resistance and diabetes associated with obesity. Future studies in childhood obesity may target these SREBP effects.
Technical Abstract: Continuous infusion of ethanol into the stomach of nutritionally supported rats results in pulses of blood and urine ethanol with a 6-7 day cycle rather than the steady-state normally observed with chronically infused drugs. The cycle is driven by cyclical changes in transcription of liver ADH Class I, the major enzyme involved in alcohol metabolism. Electrophoretic mobility shift analysis of the ADH I gene promoter revealed decreased binding of nuclear proteins from ethanol-exposed rats to two canonical sterol response element sites at -63 to -53 and -52 to -40 base pairs relative to the transcription start site on the ADH promoter (p<0.05). Sterol response elements on genes bind a family of transcription factors: the SREBPs which are involved in fatty acid and cholesterol metabolism, both of which are known to be disrupted by alcohol. Specificity of the transcription factor SREBP-1 for the response element was confirmed by chromatin immunoprecipitation (ChIP). Transcriptional inhibition of ADH by SREBP-1 was confirmed by showing the stimulatory effects of SREPB-1 antibodies in in vitro transcription assays. SREBP-2 antibodies had no effect on in vitro transcription of ADH. Although ethanol treatment elevated the SREBP target genes fatty acid synthase and cholesterol 7-alpha hydroxylase (p<0.05) in liver, this appears to be due to increased expression of SREBP-2 (p<0.05). Mature SREBP-1 protein levels in nuclear extracts were suppressed by ethanol (p<0.05), but SREPB-1 mRNA levels were unaffected suggesting an ethanol inhibition of post-translational processing of this transcription factor.