Mechanisms of Sensitization to TNF hepatotoxicity in ALD

ALD 中 TNF 肝毒性的致敏机制

• 批准号: 7123084
• 负责人: ZHENYUAN SONG
• 金额: $ 10.24万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123084
• 关键词: S adenosylmethionine; alcoholic beverage consumption; alcoholic fatty liver; alcoholic liver cirrhosis; alcoholism /alcohol abuse; cysteine endopeptidases; enzyme activity; enzyme inhibitors; enzyme linked immunosorbent assay; gel mobility shift assay; hepatotoxin; laboratory rat; liver toxic disorder; methionine; polymerase chain reaction; terminal nick end labeling; tissue /cell culture; transmethylation; tumor necrosis factor alpha

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.

描述（由申请人提供）：酒精性肝病（ALD）在美国一直是一个重要的健康问题。肝脏蛋氨酸代谢异常是ALD的一种获得性代谢异常，慢性酒精摄入对肝脏蛋氨酸代谢的影响最初似乎是矛盾的。尽管饮酒导致肝脏s -腺苷蛋氨酸（SAMe）缺乏，但它会升高肝脏同型半胱氨酸水平，这是SAMe代谢的产物。