非酒精性脂肪性肝病（NAFLD）是指肝实质细胞脂肪沉积为主要特征的临床病理综合征。近年来的研究发现，在肥胖小鼠肝脏中，自噬功能显著降低。这与自噬的主要蛋白水平降低和自噬溶酶体形成受阻有关。TFEB是一个调节自噬和溶酶体相关基因表达的主要转录因子。在饥饿的小鼠肝脏中，TFEB表达受核受体PPARɑ转录调控升高。我们前期的研究发现，在高脂饮食诱导的肥胖大鼠肝脏中，TFEB的mRNA和蛋白水平均降低。同时，TFEB的多个靶基因表达也降低，提示TFEB在NAFLD的病理过程中起重要作用。在本项目中，我们将通过细胞、动物和临床几个层次，探讨在NAFLD中，TFEB失活是否导致自噬降低和肝脂肪累积。同时，研究药物干预激活PPARɑ是否可以通过上调TFEB，改善自噬和缓解肝脏脂肪累积。本研究为治疗NAFLD寻找潜在药物靶点。

Non-alcoholic fatty liver disease (NAFLD) is defined as a common clinicopathologic condition characterized by lipid deposition in hepatocytes and compromises a wide spectrum of liver damage. Recent studies have revealed that the autophagic function is reduced, which is associated with a decrease in autophagy-related proteins and blockage of autophagosome-lysosome fusion in livers of obese mice with hepatic steatosis. TFEB（Transcription factor EB）is a master regulator of autophagy- and lysosome-related genes. The expression of TFEB in the liver of mice is positively regulated by a nuclear receptor PPARɑ during fasting. Our recent study demonstrated that the expressions of TFEB as well as its targeted genes were reduced in livers of mice fed high-fat diet, implicating a role of TFEB in pathogenesis of NAFLD. In this study, using cell culture, animal models and clinic samples, we will clarify whether loss of TFEB function results in reduced autophagy and lipid accumulation in NAFLD. Meanwhile, we will investigate whether application of PPARɑ agonists improves autophagy and reduces lipid accumulation in livers. Our study try to find a potential target for treatment of NAFLD.