The Role of Autophagy in Alcohol-Induced Liver Injury

描述（由申请人提供）：酒精滥用和消费是肝脏疾病的主要原因，是美国的一个主要健康问题。这种疾病的特征是脂肪肝、肝炎、纤维化和肝硬化。肝硬化是美国第十一大死亡原因。酒精滥用和酒精中毒约占肝硬化引起的所有死亡的50%。近年来的研究表明，氧化应激诱导的线粒体损伤和细胞凋亡参与了酒精性肝病（alcoholic liver diseases，ALD）的发生发展，但其发病机制尚未完全阐明。据估计，28%的成年人有高风险的饮酒模式，如酗酒（1）。虽然有大量关于过量饮酒引起的肝毒性的研究，但饮酒过多和过快（暴饮）对肝脏的影响却很少研究。自噬是一种遗传程序化的、进化上保守的过程，其降解长寿命的细胞蛋白和受损的细胞器，包括线粒体。乙醇是否可以诱导自噬，或者自噬是否在乙醇诱导的肝脏发病机制中起作用尚不清楚。我们已经获得的证据表明，乙醇处理肝细胞可以导致自噬体的积累。我们假设乙醇可以诱导自噬，这对于去除由乙醇引起的损伤线粒体是重要的;并且自噬可以调节乙醇诱导的细胞死亡。预计这项工作将产生关于自噬在酒精发病机制中的作用的新发现。 公共卫生相关性：酒精滥用和消费是肝脏疾病的主要原因，是美国的一个主要健康问题。自噬已被证明能够调节细胞死亡和包括线粒体在内的细胞器的周转，这是酒精性肝病的重要机制。阐明自噬和细胞死亡如何整合在酒精性肝病中的分子机制将有助于产生新的治疗策略。

DESCRIPTION (provided by applicant): Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States. The characteristics of this disease are fatty liver, hepatitis, fibrosis, and cirrhosis. Cirrhosis is the eleventh leading cause of death in the United States. Alcohol abuse and alcoholism accounts for approximately 50 % of all death induced by liver cirrhosis. However, the pathogenesis of alcoholic liver diseases (ALD) is not completely understood although recent researches suggest that oxidative stress- induced mitochondrial damage and apoptosis are involved in the development of ALD. It is estimated that 28% of the adult population has a high-risk drinking pattern, such as binge drinking (1). Although there are large number of studies regarding the hepatotoxicity due to excessive drinking, the effects of drinking too much and too fast (binge drinking) on the liver have been sparingly studied. Autophagy is a genetically programmed, evolutionarily conserved process that degrades long-lived cellular proteins and damaged organelles including mitochondria. Whether ethanol can induce autophagy, or whether autophagy plays a role in alcohol-induced liver pathogenesis is not known. We have obtained evidence that ethanol treatment of hepatocytes can lead to the accumulation of autophagosomes. We hypothesize that ethanol can induce autophagy which is important for the removal of damaged mitochondria caused by ethanol; and that autophagy can modulate ethanol-induced cell death. It is anticipated that this work will generate novel finding regarding the role of autophagy in alcoholic pathogenesis. Public Health Relevance: Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States. Autophagy has been shown to be able to regulate cell death and organelle turn over including mitochondria, which is an important mechanism in alcoholic liver disease. Elucidating the molecular mechanisms of how autophagy and cell death are integrated in alcoholic liver disease will help to generate novel therapeutic strategies.