Chronic alcohol abuse leads to a series of health problems that cost thousands of lives annually and accounts for billions of dollars each year in medical expenditures. The biological effects of alcohol are related to the dose consumed, the blood and tissue concentrations obtained, the duration that tissues are exposed to high ethanol concentrations, and the frequency of alcohol intake. There are, of course, other variables such as; gender, age, genetic predisposition, underlying health effects, etc. However, the tissue alcohol concentrations and duration of exposure are by far the most important aspects of alcohol-related health effects and are in good part related to the metabolism of alcohol. Alcohol metabolism is fundamental to alcohol's actions and although the enzymes that metabolize alcohol have been known for years, the mechanisms by which they are regulated are not well understood. Hepatic Class I Alcohol Dehydrogenase (ADH) is the principal alcohol-metabolizing enzyme and is responsible for as much as 95%of alcohol conversion to the toxic metabolite acetaldehyde and is the first step in the eventual clearance of alcohol from the body. Until recently, it was thought that alcohol could not signal the liver to synthesize more ADH when alcohol concentrations became high. We have used the intragastric rodent model of alcoholic liver disease (ALD) to study the molecular regulation of Class I ADH during times when alcohol concentrations become high, such as would occur in alcoholics, and found that alcohol can indeed cause the liver to produce sufficiently more Class I ADH to drive alcohol concentrations down to less toxic concentrations. These findings have far reaching implications for such areas as; 1) the central nervous system (alcohol dependence & tolerance); and 2) the liver (ALD, alcohol-induced diabetes and obesity). Furthermore, we have proposed a plausible mechanism underlying this important process. The major focus of this renewal is regulation of the gene encoding Class I ADH during chronic ethanol intake. Our overall working hypothesis is that chronic ethanol intake causes increased production (expression) of Class I ADH by disrupting hormonal systems that ultimately regulate rat Class I ADH production via intracellular signals (called signal transduction pathways) that are commonly used by hormones (especially insulin) to regulate gene actions. We will employ a series of in vitro (cell culture, molecular biological and biochemical) and in vivo (intragastric infusions of ethanol-containing diets to rats) procedures that we have standardized in our lab to study alcohol metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008645-16
Application #
7087918
Study Section
Special Emphasis Panel (ZRG1-DIG-B (04))
Program Officer
Gentry, Thomas
Project Start
1990-06-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
16
Fiscal Year
2006
Total Cost
$319,804
Indirect Cost
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Ronis, Martin J J; Mercer, Kelly; Suva, Larry J et al. (2014) Influence of fat/carbohydrate ratio on progression of fatty liver disease and on development of osteopenia in male rats fed alcohol via total enteral nutrition (TEN). Alcohol 48:133-44
Ronis, Martin J J; Hennings, Leah; Stewart, Ben et al. (2011) Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 300:G109-19
Ronis, Martin J; Korourian, Soheila; Blackburn, Michael L et al. (2010) The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat. Alcohol 44:157-69
He, Ling; Marecki, John C; Serrero, Ginette et al. (2007) Dose-dependent effects of alcohol on insulin signaling: partial explanation for biphasic alcohol impact on human health. Mol Endocrinol 21:2541-50
Ronis, Martin J J; Wands, Jack R; Badger, Thomas M et al. (2007) Alcohol-induced disruption of endocrine signaling. Alcohol Clin Exp Res 31:1269-85
Baumgardner, January N; Shankar, Kartik; Korourian, Sohelia et al. (2007) Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition. Am J Physiol Gastrointest Liver Physiol 293:G355-64
He, Ling; Simmen, Frank A; Mehendale, Harihara M et al. (2006) Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane. Role of TRB3 in inhibition of Akt/protein kinase B activation. J Biol Chem 281:11126-34
Badger, Thomas M; Hidestrand, Mats; Shankar, Kartik et al. (2005) The effects of pregnancy on ethanol clearance. Life Sci 77:2111-26
Wahl, Elizabeth C; Perrien, Daniel S; Aronson, James et al. (2005) Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: a role for the tumor necrosis factor signaling axis. Alcohol Clin Exp Res 29:1466-72
Ronis, Martin J J; Butura, Angelica; Sampey, Brante P et al. (2005) Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radic Biol Med 39:619-30

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