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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #187212

Title: ETHANOL INDUCES AND INSULIN INHIBITS ALCOHOL DEHYDROGENASE CLASS 1 IN FGC-4 CELLS: BOTH APPEAR TO WORK THROUGH SREBP-1

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

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 11/15/2005
Publication Date: 3/15/2006
Citation: He, L., Simmen, F.A., Ronis, M.J., Badger, T.M. 2006. Ethanol induces and insulin inhibits alcohol dehydrogenase class 1 in fgc-4 cells: Both appear to work through srebp-1 [abstract]. The Toxicologist. 90(1):1368.

Interpretive Summary: Alcohol abuse has been linked to increased incidence of type II diabetes. This is accompanied by development of cellular resistance to the actions of the hormone insulin. We have previously shown that long-term alcohol treatment in rats can increase ethanol breakdown via increased expression of the enzyme alcohol dedydrogenase (ADH) in the liver. In the current study we have reproduced the effects of ethanol on ADH expression in cell culture and demonstrated that the mechanism of action involves interference with an insulin signaling pathway involving the transcription factor SREBP-1c. These data are consistent with development of insulin resistance in liver cells exposed to levels of ethanol commonly found in alcoholics and may explain why alcoholics clear alcohol from the body faster than people who do not drink.

Technical Abstract: We have previously reported that chronic feeding of alcohol-containing diets (via intragastric infusion) to Sprague-Dawley rats induces hepatic alcohol dehydrogenase (ADH) Class 1 by interfering with signaling via the sterol regulatory element binding protein (SREBP-1). We have studied the effects of alcohol in vitro using a highly differentiated rat hepatoma cell line (FGC-4). Cells cultured in the presence of ethanol (50 mM) had elevated (P<0.05) ADH mRNA compared with cells incubated without ethanol. Incubation of FGC-4 cells with insulin (1 nM) stimulated production of nSREBP-1, and this was blocked by 50 mM ethanol. Furthermore, insulin decreased ADH mRNA (P<0.05) in a dose-responsive manner (0.1 – 10 nM), and this decrease was blocked by ethanol (50 mM). The doses of insulin used were in the physiologic range, and the ethanol dose was equal to that normally achieved in the intragastric model. These results demonstrate that: 1) ethanol induces ADH in FGC-4 cells in a fashion similar to that reported in vivo in rats, suggesting these cells are an excellent model to study ethanol-induced gene effects; and 2) insulin negatively regulates hepatic ADH. These results, when combined with our previous data, suggest that ethanol induces ADH via interfering with insulin signaling through SREBP-1.