Mechanisms of Alcoholic Liver Disease

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。有充分的证据表明，饮酒会加速肝炎病毒感染引起的肝脏疾病的发生和进展。我们的实验室旨在研究慢性乙醇消耗如何增强其他毒素或病毒诱导的肝损伤，并研究酒精诱导的肝损伤的分子机制。我们已经证明IL-6在酒精性肝损伤、非酒精性脂肪性肝病、脂肪性肝移植和T细胞肝炎的几种小鼠模型中对肝损伤起重要的保护作用。我们的研究结果还表明，IL-6治疗可以改善酒精喂养小鼠、高脂肪喂养小鼠和转基因ob/ob小鼠的脂肪肝疾病。据认为，IL-6的作用是通过激活信号换能器和转录激活因子3 （STAT3）介导的。目前，我们正在通过肝脏特异性和巨噬细胞/中性粒细胞特异性STAT3敲除小鼠，探索IL-6对脂肪肝保护作用的分子机制。

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. 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 IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. Our findings also showed that treatment with IL-6 ameliorates fatty liver disease in alcohol-fed mice, high-fatdiet fed mice, and genetically modified ob/ob mice. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). Currently, we are exploring the molecular mechanisms underlying the protective effect of IL-6 in fatty liver disease by using liver specific and macrophage/neutrophil-specific STAT3 knock out mice. In addition, we are also collaborating with Dr. George Kunos and Dr. Pal Pacher from NIAAA 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.