脂滴蛋白Perilipin 5调控脂周线粒体PDM形成在非酒精性脂肪性肝纤维化进展中的作用及机制研究

非酒精性脂肪性肝病NAFLD目前仍缺乏有效的药物。脂肪细胞中的脂滴可以募集游离的胞浆线粒体，形成脂周线粒体PDM，增强线粒体功能，脂滴蛋白Plin5在其中发挥调控作用。但肝细胞中异位储存的脂滴在NAFLD发病中的作用及机制仍不清楚。我们前期发现，与单纯脂肪变NAFL相比，NASH肝纤维化小鼠肝组织Plin5的表达显著下降，且与线粒体功能及肝组织病变程度相关。本课题首先通过NAFLD患者肝穿样本及小鼠模型，明确Plin5与PDM、线粒体功能、炎症及肝纤维化的相关性；接下来应用Plin5基因敲除、过表达小鼠及体外NAFLD模型直接干预Plin5表达，明确Plin5对PDM的调控及其在NAFL进展为NASH过程中的关键作用；最后探讨上游PPAR-α通路及互作蛋白在Plin5调控PDM形成中的作用，深入研究其分子调控机制。从脂滴调控线粒体功能的角度，为NAFLD的防治提供实验基础及理论依据。

Non-alcoholic fatty liver disease (NAFLD) still lacks effective drugs. Lipid droplets in adipocytes can recruit free cytoplasmic mitochondria to form peri-droplet mitochondria (PDM), which promote the function of mitochondria. The lipid droplet protein perilipin 5 (Plin5) plays a regulatory role in it. However, the role and mechanism of the lipid droplets stored ectopically in hepatocytes in the pathogenesis of NAFLD is still unclear. We previously found that compared with NAFL, the expression of Plin5 decreased significantly in liver tissue of mice with NASH related liver fibrosis, and it was significantly correlated with the function of mitochondria and the severity of liver tissue injury. In this study, we will clarify the correlation between Plin5 and PDM, mitochondrial function, inflammation and liver fibrosis through liver puncture samples of NAFLD patients and animal models. Next, Plin5 gene knockout, over-expressing mice and in vitro NAFLD cell model will be used to clarify the key role of Plin5 in the formation of PDM and the progression of NAFL to NASH through interfering with the expression of Plin5. Finally, the role of upstream PPAR-α pathway and interaction proteins in the formation of PDM regulated by Plin5 will be explored to elucidate the molecular mechanism. This study will provide experimental foundation and theoretical basis for the prevention and treatment of NAFLD from the perspective of lipid droplets regulating mitochondrial function.