本课题组已发现并证实中药成分复方（京尼平苷合绿原酸，GC方）对非酒精性脂肪肝（NAFLD）有很好的防治效应。近与美国加州大学合作研究发现GC方对饱和性脂肪酸诱导的小鼠肝细胞线粒体损伤具有良好的保护作用。近发现，细胞周期蛋白CDK能够移位至线粒体内膜和基质从而促进线粒体能量代谢和氧自由基清除能力, 发挥保护肝细胞线粒体稳态的生物学效应，在NAFLD发生发展中具重要意义。鉴此，提出“GC方可能通过影响肝细胞线粒体CDK1的表达促进线粒体能量代谢和稳态平衡，进而改善游离性脂肪酸介导的肝细胞损伤”的假说。拟通过建立线粒体导向野生型和失活突变型CDK1肝细胞模型, 结合运用饱和性脂肪酸诱导线粒体损伤的细胞模型和高脂饮食诱导的NAFLD动物模型，针对GC方促进线粒体能量代谢降低肝细胞氧化应激损伤等关键环节，探讨GC方影响CDK1及其线粒体稳态，抗线粒体损伤等防治NAFLD的机制、靶点以及配伍特

Our previouse work has shown that the compounds Geniposide and Chologenic acid (GC) in Chinese herbal are the key compound that can be used to prevent and treat non-alcoholic fatty liver disease (NAFLD). Via collarabration with Dr. Jian jian Liat University of California Davis Medical Center, USA, we found that GC may reduce saturated fatty acid-induced liver cell injury by enhancing mitochondrial homeostasis. Recent findings from his lab revealed that the cell cycle regulator CDK1 can relocate into the inner membrane and matrix of the mitochondria and improve the cell energy biosynthesis and antioxidant ability, thus improve the mitochondrial bioenergetics and homeostasis, which may play a key role in GC-mediated protection against NAFLD. We hypothesized that “GC could improve mitochondria energy biosynthesis and hemostasis, thus significanly reduce free fatty acid induced hepatocyte damage by inducing mitochondrial CDK1 activation”.In the proposed study, we will further elucidate the molecular mechanism underlgying GC-mediated CDK1 activation and mitochondrial homeostasis in NAFLD. We will use a specific mitochondrial gene transfection model with mitochondria-trageted CDK1 or its mutant form (MTS-CDK1-mut) in mouse liver cells. This model will be tested with saturated fatty acid induced hepatic mitochondria damage and high fat-enriched diet NAFLD mouse model. These results will help to elucidate the molecularmechnisms, therapeutic targets and compatibility of GC, which will provide a critical platform for the further development of new effective combination of herval compounds to treat NAFLD.