内质网-MAMs-线粒体轴在脂稳态失衡诱发小鼠脂肪肝中肝细胞早衰机制研究

非酒精性脂肪性肝病（NAFLD）是当前研究的热点。申请者在之前国基金中发现，小鼠脂肪肝中存在明显肝细胞早衰，其应对缺血再灌注损伤的能力显著削弱，这可能是导致NAFLD临床预后不良的重要原因。我们发现肝细胞早衰与脂代谢紊乱密切相关。线粒体是细胞衰老的中心环节，其功能受内质网调控。内质网和线粒体可通过直接的、特异性的线粒体相关内质网膜（MAMs）进行快速的物质交换，这可能是高脂诱导肝细胞早衰的重要机制。目前对内质网-MAMs-线粒体轴的研究刚起步。肝细胞早衰与NAFLD预后不良之间的关系与机制尚未见报道。研究内容：1.高脂诱导早衰机制以及内质网-MAMs-线粒体轴在其中的作用；2.调控内质网-MAMs-线粒体轴以影响高脂诱导的肝细胞早衰并改善NAFLD临床预后。本项目拟通过对内质网-MAMs-线粒体轴在脂肪肝肝细胞早衰中的机制研究，揭示NAFLD患者临床预后不良的原因并探索可能的干预措施。

Nonalcoholic fatty liver disease (NAFLD) is a hot and difficult point in clinical medical research. In our previous National Science Foundation Project, the applicant found that there was significant premature senescence of hepatocyte in the liver of NAFLD mice, and its ability to cope with ischemia-reperfusion injury was significantly weakened, which may be an important reason for the poor clinical prognosis of NAFLD. Our previous study found that this premature senescence may be closely related to the disorder of liver lipid metabolism. Mitochondria are the central link of cell aging, and the function of mitochondria is regulated by endoplasmic reticulum (ER). ER and mitochondrion can exchange substances directly and specifically through mitochondrial associated endoplasmic reticulum (MAMs), which may be an important mechanism of high fat-induced premature senescence. At present, the study of the ER-MAMs-mitochondrial axis has just started. The relationship between hepatocyte premature senescence in fatty liver and poor prognosis of NAFLD has not been reported. Research contents: 1. The mechanism of high-fat induced premature senescence and the role of the ER-MAMs-mitochondrial axis in it; 2. Whether the regulation of the ER-MAMs-mitochondrial axis can affect the high-fat induced premature senescence of hepatocytes and improve the clinical prognosis of NAFLD. This project aims to study the mechanism of the ER-MAMs-mitochondrial axis in the hepatocyte premature senescence, reveal the causes of poor clinical prognosis in NAFLD patients and explore possible intervention measures.