Mechanisms of Sensitization to TNF hepatotoxicity in ALD

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DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) continues to be an important health problem in the United States. Abnormal hepatic methionine metabolism is an acquired metabolic abnormality in ALD and the effects of chronic alcohol intake on hepatic methionine metabolism are initially seemingly paradoxic. Whereas alcohol consumption causes hepatic deficiency of S-adenosylmethionie (SAMe), it elevates hepatic homocysteine levels, a product of SAMe metabolism. Decreased SAMe levels and elevated homocysteine levels may contribute to alcohol induced liver injury. The effect of alcohol on S-adenosylhomocysteine (SAH) levels, another metabolite in the methionine metabolism pathway, has received little investigative attention. It is our working hypothesis that tumor necrosis factor (TNF) in conjunction with certain metabolic abnormalities observed in ALD, such as altered intracellular methylation status due to abnormal methionine/SAMe/SAH metabolism play an etiologic role in the development of liver injury in ALD. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, generation of reactive oxygen intermediates, activation of Kupffer cell NFkB with increased TNF production, decreased hepatocyte MAT activity with subsequent SAMe deficiency, increased S-adenosylhomocysteine (SAH) concentrations, inhibition of transmethylation reactions, decreased hepatic methylation status, elevated expression/ activation/activity of proteins sensitive to intracellular methylation status such as caspase-8, mitochondrial dysfunction, increased susceptibility to hepatic TNF cytotoxicity, and subsequent liver injury. In this proposal, we will evaluate inhibition of hepatic transmethylation reactions by chronic alcohol exposure as a mechanism for hepatic sensitization to TNF-induced cytotoxicity in a relevant model of ALD. The specific objectives of this project are as follows: 1. Evaluate the effects of inhibition of hepatic transmethylation reactions on "sensitization" to TNF hepatotoxicity; 2. Investigate possible mechanisms by which inhibition of transmethylation reactions sensitizes hepatocytes to TNF hepatotoxicity; and 3. Evaluate the effects of chronic alcohol consumption (+/- SAMe supplementation) on hepatic methylation status and sensitization to TNF-hepatotoxicity in rats intragastrically fed alcohol. This research will be performed with structured mentoring support and a detailed training program designed to maximize my opportunity to become an independent NIH-funded investigator.