杨梅素通过SIRT1-T-bet轴调节肝脏ILC1细胞的免疫功能防治NASH的作用及机制研究

非酒精性脂肪性肝炎（NASH）严重威胁人类健康，但缺乏理想防治措施。肝脏区域免疫稳态失调是单纯性脂肪肝向NASH发生发展的关键环节，而依赖于转录因子T-bet的1型固有淋巴样细胞（ILC1）在维护肝脏区域免疫稳态中起关键作用，可能成为防治NASH的新靶点。研究表明，杨梅素能改善高脂饮食诱导小鼠的肝脏脂肪变性及炎症进程；课题组前期研究发现，杨梅素可通过AMPK提高SIRT1表达改善线粒体功能，推测杨梅素可能成为防治NASH的理想植物化学物。结合相关预实验结果，我们提出“杨梅素可能通过SIRT1-T-bet轴调节肝脏ILC1细胞免疫功能防治NASH发生发展”的科学假说。本项目拟利用高脂诱导小鼠模型以及SIRT1-/-小鼠，结合流式细胞术等方法，阐明杨梅素通过调节肝脏ILC1细胞免疫功能维持肝脏区域免疫稳态，改善NASH发生发展的作用机制。该课题将为防治NASH提供新靶点和膳食营养干预新策略。

Nonalcoholic steatohepatitis (NASH) continues to threaten human health, but there are no ideal prevention and treatment strategies. Recent researches have found the imbalance of regional immune homeostasis plays a key role in the development of NAFL to NASH. ILC1 depending on T-bet plays a key role in the regulation of immune homeostasis in liver. So it may be a new target for the prevention and treatment of NASH. Previous studies have found that myricetin can improve liver fatty degeneration and inflammatory cell infiltration as well as the cytokine in high-fat diet induced mice. According to our researches, myricetin could increase the expression of SIRT1 to improve the mitochondrial structure and function as well as biosynthesis through the AMPK pathway. Combined with the relevant researches, we hypothesize that myricetin could regulate the immune function of ILC1 cells in liver through sirt1-t-bet axis to improve the early development of NASH. In this project, the high-fat induced mice model and SIRT1-/- mice were used. Combining with flow cytometry and other methods, we aim to clarify the mechanism of myricetin regulating the immune function of ILC1 cells in the liver through SIRT1-T-bet axis and maintaining the regional immune homeostasis of the liver in improving the occurrence and development of NASH. This study has an important significance of theoretical and application prospects for the prevention of NASH.