Mechanisms of Alcoholic Liver Disease

饮酒是世界范围内慢性肝病的主要病因。人类酒精性肝病的形态学谱包括脂肪肝、酒精性肝炎和肝硬化。在啮齿类动物中，乙醇胃内输注4-5周会导致脂肪变性、炎症和较低程度的肝脏纤维化，而喂食含乙醇的Lieber-DeCarli液体饲料不会导致除脂肪变性外的显著肝损伤。有趣的是，在人类中，只有一小部分重度饮酒者（10-15%）会发生酒精性肝损伤，这强烈表明酒精是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诱导的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、饮酒的剂量和持续时间、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脏铁超载。有充分的证据表明，饮酒会加速肝炎病毒感染引起的肝病的发展和进展。我们的实验室研究慢性酒精消耗如何增强其他毒素或病毒引起的肝损伤，并研究酒精诱导的肝损伤的分子机制。我们已经证明，酒精消耗加速T细胞和MCMV病毒介导的肝炎，IL-6治疗可改善小鼠酒精性脂肪肝。目前，我们正在研究（1）IL-6/STAT 3在酒精性肝损伤和移植中的肝保护作用，（2）饮酒通过调节先天免疫对肝纤维化的影响，（3）饮酒对肝祖细胞的影响。我们还与乔治Kunos博士合作研究canabinoid在酒精性肝病中的作用，并与NIDDK的Jake Liang博士合作研究酒精和肝炎病毒蛋白在肝损伤中的相互作用。

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 by hepatitis virus infection. Our lab is to study how chronic ethanol consumption potentiates liver injury induced by other toxins or viruses and to study the molecular mechanisms underlying alcohol-induced liver injury. We have demonstrated that alcohol consumption accelerates T cell- and MCMV virus-mediated hepatitis and that treatment with IL-6 ameliorates alcoholic fatty liver disease in mice. Currently, we are studying (1) the hepatoprotective effect of IL-6/STAT3 in alcoholic liver injury and transplantation, (2) the effect of alcohol drinking on liver fibrosis via modulation of the innate immunity, (3) the effect of alcohol drinking on liver progenitor cells. We are also collaborating with Dr. George Kunos to investigate the role of canabinoid in alcoholic liver disease, and with Dr. Jake Liang from NIDDK to study the interaction of alcohol and hepatitis viral proteins in liver injury.