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Alcoholism is of major public health concern worldwide. Alcoholic liver disease (ALD) encompasses a continuum of pathophysiologic conditions ranging from fatty liver (steatosis) to alcoholic hepatitis and cirrhosis. Although steatosis is very common among heavy drinkers, only about 20 percent of alcohol abusers develop serious liver damage. Thus, the liver of the majority of alcoholics withstands the burden of heavy drinking for decades while other individuals develop liver disease after only a few years of alcohol abuse. The factors that precipitate ALD in those disease-prone individuals and the factors that protect the majority of alcoholics from developing ALD are largely unknown. Furthermore, there appears to be a striking gender difference in susceptibility, with women developing cirrhosis after shorter periods and lower levels of alcohol intake than men. While it is clear that some of the pathological consequences of drinking can be attributed to ethanol directly, others appear to be indirect effects mediated via ethanol metabolites, in particular free radical produced as a consequence of ethanol metabolism via a minor pathway catalyzed by the cytochrome P450 enzyme CYP2E1. There is considerable evidence that ethanol/nutritional interactions are important mediators in many of the processes leading to ALD. Ethanol, unsaturated fat and increases in fat/carbohydrate ratio all result in induction of CYP2E1. It is our hypothesis that CYP2E1-mediated radical formation is the principal factor involved in the etiology of ethanol-induced liver injury, possibly through activation local macrophages (Kupffer cells) to release pro-inflammatory cytokines. Furthermore, we postulate that diet effects on CYP2E1 expression and inducibility by ethanol underlie the effects of diet on development of ethanol-induced hepatotoxicity. This proposal is the joint effort of one American laboratory in Little Rock, Arkansas and laboratories in Finland, Sweden and Italy. The overall goals are to develop and validate a new low carbohydrate liquid diet rat model for ethanol-induced liver injury in a side comparision with the well-established intragastric-infusion model. Comparison of the models will focus on three important variables which may influence the course of ALD: 1) diet; 2) gender; and 3) activation of Kupffer cells.

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