Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 10/3/2004
Publication Date: 3/15/2005
Citation: He, L., Simmen, F.A., Ronis, M.J., Badger, T.M. Ethanol has biphasic effects on expression of sterol regulatory element binding protein-1 (srebp-1) in rat fgc-4 hepatoma cells with inhibition at high doses resulting in induction of ADH class I. The Toxicologist. 84(S-1): 392. Interpretive Summary: Alcohol is consumed by millions of Americans and represents a significant portion of the daily caloric intake in many people. There are known beneficial and adverse effects of alcohol consumption. Alcohol is cleared from the body after consumption by enzymes, and the main enzyme is known as ADH. ADH also has other functions in the body and anything that alters its levels or function could potentially affect health. We have been studying how alcohol increases ADH and we found that alcohol can alter ADH levels by either increasing or decreasing a protein called SREBP-1. At low doses of alcohol, SREBP-1 is increased, but higher doses will decrease SREBP-1. This is important because SREBP-1 is also important in insulin actions and is associated with disorders such as diabetes. Thus, these studies are the first in a series of future studies to determine the beneficial and adverse effects of alcohol consumption.
Technical Abstract: SREBPs are transcription factors which regulate fatty acid and cholesterol metabolism. Alcohol has long been known to disrupt lipid metabolism and produce fatty liver. However, effects of ethanol on SREBP expression have been an area of dispute with some investigators reporting a significant increase and some a decrease. In the current study we examined the dose responsive effects of ethanol on expression of the transcription factor SREBP-1 in the rat FGC-4 hepatoma cell line with which we previously demonstrated ethanol induction of the major alcohol metabolizing enzyme ADH class I. Ethanol had a biphasic effect on expression of the mature form of SREBP-1 protein in cellular homogenates. At low doses of ethanol (< 10 mM) SREBP-1 expression was increased (p < 0.05) with a 2-fold increase evident at 5 mM. In contrast, at higher doses of ethanol a dose-dependent decrease in SREBP-1 expression was observed and this correlated with increased expression of ADH class I (p < 0.05). The liver X-receptor agonist T0901317, a known activator of SREBP-1 transcription, was shown to produce a dose-dependent decrease in ADH expression which was completely abolished by ethanol. These data confirm in an in vitro model that SREBP-1 is a negative regulator of ADH transcription and that ethanol at high doses induces ADH via suppression of SREBP-1 protein expression.