Mechanisms of Alcoholic Liver Disease: Dis-regulation of

饮酒是全球慢性肝病的主要病因。人类酒精性肝病的形态谱包括脂肪肝、酒精性肝炎和肝硬变。在啮齿类动物中，灌胃乙醇4-5周会导致肝脏脂肪变性、炎症，并在较小程度上导致肝纤维化，而饲喂含乙醇的Lieber-DeCarli液体饲料除脂肪变性外，不会引起明显的肝损伤。有趣的是，在人类中，只有一小部分酗酒者(10%-15%)出现酒精性肝损伤，这有力地表明酒精是发展为慢性肝病的辅助因素。越来越多的证据表明，许多遗传和获得性因素与个体对酒精性肝损伤的易感性有关。这些因素包括慢性病毒感染、营养因素、饮酒剂量和饮酒时间、饮酒模式、饮酒开始年龄、细胞因子和酒精代谢酶基因多态性、性别、组织相容性抗原、免疫因素、酒精成瘾遗传易感性和肝脏铁超载。已有文献表明，饮酒加速了肝病引起的肝炎病毒感染的发生和发展。我们的实验室旨在研究慢性酒精摄入是如何通过细胞因子信号的失调来加强其他毒素或病毒引起的肝损伤的。我们已经证明(1)酒精消费通过破坏核因子-kappaB和STAT信号通路加速T细胞介导的肝炎，(2)IL-6治疗改善了小鼠的酒精性脂肪肝。

Alcohol consumption is a major etiology of chronic liver disease worldwide. The morphological spectrum of human alcoholic liver disease includes fatty liver, alcoholic hepatitis, and cirrhosis. In rodents, intragastric infusion of ethanol for 4-5 weeks leads to steatosis, inflammation, and to a less extent fibrosis in the liver, whereas feeding Lieber-DeCarli liquid diet containing ethanol does not cause significant liver injury except steatosis. In humans, interestingly, only a small percentage of heavy drinkers (10-15%) developed alcoholic liver injury, strongly suggesting that alcohol is a cofactor for developing chronic liver disease. Accumulating evidence suggests that many genetic and acquired factors are implicated in the susceptibility of the individual to alcohol-induced liver injury. These factors include chronic viral infection, nutritional factors, the dose and duration of alcohol consumption, pattern drinking, age of onset of drinking, genetic polymorphisms of cytokines and alcohol-metabolizing enzymes, gender, histocompatibility antigens, immunological factors, genetic predisposition to alcohol addiction, and hepatic iron overload. It has been well documented that alcohol consumption accelerates the development and progression of liver disease induced hepatitis virus infection. Our lab is to study how chronc ethanol consumption potentiates liver injury induced by other toxins or virus via dis-regulation of cytokine signals. We have demonstrated (1) that alcohol consumption accelerates T cell-mediated hepatitis via dis-regulation of NF-kappa B and STAT signaling pathways, (2) treatment with IL-6 ameliorates alcoholic fatty liver disease in mice.