非酒精性脂肪肝NAFLD危害日益严重，因对其发生发展关键环节缺乏了解，迄今尚无有效治疗措施。虎杖临床治疗NAFLD有优势，但作用机理尚不明确。果糖引起NAFLD与氧化应激密切相关。miR-200a可调控Keap1激活抗氧化应激转录因子Nrf2。我们前期工作发现果糖诱导肝细胞ROS-TXNIP氧化应激通路介导炎症信号激活和脂代谢紊乱，下调Nrf2核蛋白水平；证实虎杖主要成分虎杖苷可逆转果糖诱导NAFLD、miR-200a低表达、氧化应激和炎症。本项目拟进一步研究miR-200a低表达介导Keap1-Nrf2通路抑制抗氧化酶等基因表达，诱导ROS-TXNIP促进炎症和脂代谢紊乱新途径，及miR-200a所起重要作用；探询虎杖水提取物和虎杖苷调控miR-200a表达介导Keap1-Nrf2通路干预NAFLD新机制、新靶点。佐证工作假说，为虎杖治疗NAFLD及相关转化医学研究提供理论和实验基础。

Non-alcoholic fatty liver disease (NAFLD) is increasingly serious. Lack of understanding of the key link for NAFLD pathogenesis, so far there are no effective therapeutic measures. In the clinic of TCM, Rhizoma Polygoni Cuspidati has its special advantage for the treatment of NAFLD, however, its underlying molecular mechanisms are incompletely understood. Fructose-induced NAFLD is associated with oxidative stress. miR-200a activates antioxidant transcription factor Nrf2 by mediating Keap1. Our previous studies found that fructose induced hepatocyte ROS-TXNIP oxidantive stress pathway to mediate inflammatory signaling and lipid metabolism disorder, and down-regulated nuclear Nrf2 protein levels. Moreover, polydatin, a main constituent of Rhizoma Polygoni Cuspidati, was preliminarily confirmed to restore fructose-induced NAFLD, as well as miR-200a down-regulation, oxidative stress and inflammation. This project will continue to investigate new way that miR-200a down-expression mediate Keap1-Nrf2 pathway to suppress antioxidant enzymes-related gene expression in hepatocytes, which, in turn, induce ROS-TXNIP and subsequently to cause inflammation and lipid metabolism disorder，as well as an important role of miR-200a in fructose-induced NAFLD. Furthermore, this project will explore new mechanisms and pharmacological targets for therapeutic intervention of water extracts of Rhizoma Polygoni Cuspidati and polydation on NAFLD via regulating miR-200a-mediated Keap1-Nrf2 pathway in hepatocytes. These results will sopport the hypothesis, and provide theoretical and experimental evidences for the treatment of NAFLD by Rhizoma Polygoni Cuspidati in clinic, as well as the promotion of the translational medicine research.