APR3调控线粒体稳态参与非酒精性脂肪肝发生的机制研究

非酒精性脂肪肝（NAFLD）是由糖脂代谢紊乱引发的以肝细胞脂质积累为特征的肝脏疾病，其由单纯脂肪肝（NAFL）向脂肪性肝炎（NASH）的发展是诱发严重肝脏病变的关键因素。前期研究提示线粒体紊乱和肝细胞凋亡可能是引发NAFL、NASH的内在机制，但其早期发生机制仍不明确。我们近期研究发现凋亡相关蛋白-3（APR3）在视网膜细胞中具有线粒体定位，通过直接和间接机制来调控线粒体功能参与细胞凋亡。有趣的是，在肝细胞中APR3同样具有线粒体定位，且在小鼠脂肪肝模型中的线粒体定位显著增强。更为重要的是，APR3能被NAFLD的风险因子棕榈酸诱导表达，参与其介导的肝细胞凋亡。这些结果提示APR3基因可能是参与脂肪肝早期发生发展的关键因子之一。本研究将通过基因敲除、饮食干预等手段在细胞及动物水平上阐释APR3通过调控线粒体与细胞凋亡参与NAFLD发生发展的作用机制，为疾病的防治研究提供新的靶点和理论支持。

Nonalcoholic fatty liver disease (NAFLD) is a complex liver disease that feathered with massive lipid accumulation, the progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) is the leading cause for end-stage liver disease. Previous studies have indicated that mitochondrial dysfunction and hepatic apoptosis might be the key intrinsic mechanism with limited knowledge on the detail process. Recently, we found that newly discovered apoptosis related protein-3 (APR3) can locate in mitochondria, and closely involved in regulating mitochondrial function and apoptosis activation in retinal epithelial cells. Interestingly, APR3 can also translocate into mitochondria in hepatocytes, which was significantly increased in NAFLD mice. Meanwhile, APR3 was highly induced by palmitic acid, which is the major form of free fatty acid that increased in NAFLD population. The knockdown of APR3 can prevent palmitic acid induced hepatic apoptosis. These data highly suggested the closely involvement of APR3 in the development of NAFLD. In current study, we intend to explore the detail mechanisms of APR3 in the development of NAFLD through in vitro cellular and in vivo mice studies, thereby providing new targets for intervention and treatment of NAFLD.