Mechanisms of Alcoholic Liver Disease: Dis-regulation of

饮酒是世界范围内慢性肝病的一个主要病因。人类酒精性肝病的形态学包括脂肪肝、酒精性肝炎和肝硬化。在啮齿类动物中，连续4-5周灌胃乙醇可导致肝脏脂肪变性、炎症，并在较小程度上导致肝脏纤维化，而饲喂含有乙醇的Lieber-DeCarli液体饲料除了脂肪变性外，不会造成明显的肝损伤。有趣的是，在人类中，只有一小部分重度饮酒者（10-15%）发生酒精性肝损伤，这强烈表明酒精是发生慢性肝病的辅助因素。越来越多的证据表明，许多遗传和后天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、饮酒剂量和持续时间、饮酒模式、开始饮酒的年龄、细胞因子和酒精代谢酶的遗传多态性、性别、组织相容性抗原、免疫因素、酒精成瘾的遗传易感性和肝铁超载。有充分的证据表明，饮酒会加速肝脏疾病引起的肝炎病毒感染的发生和进展。我们的实验室正在研究慢性乙醇消耗如何通过细胞因子信号失调来增强其他毒素或病毒诱导的肝损伤。我们已经证明(1)饮酒通过NF-kappa B和STAT信号通路的失调加速T细胞介导的肝炎；(2)用IL-6治疗可改善小鼠的酒精性脂肪肝疾病。

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.