木通皂苷D通过BNip3-mitophagy通路调控NAFLD肝脏脂质代谢紊乱的作用与机制研究

Non-alcoholic fatty liver disease (NAFLD) has became a global public health issue, however the exact pathogenesis has not been elucidated and there is no ideal drugs for NAFLD. Recent studies have shown that BNip3-mediated mitophagy played critical roles in the hepatic lipid metabolism, however the related mechanims of the cell signaling transduction still unknown. In the preliminary studies we have found that Akebia saponin D (ASD)could activate BNip3, improve the level of autophagy, protect mitochondrial and reduce liver lipid deposition.The significant anti-NAFLD effects of ASD may be associated with the BNip3-mitophagy signaling pathway. The project intends to predict the drug target of ASD by using oleate induced hepatic steatosis and ob/ob mice, and investigate the effect of mitophagy by interfere BNip3 and AMPK、PI3K/AKT signaling pathways. The relationship between BNip3-mitophagy and NAFLD will be studied. These researches might provide a new target, a potential drug for the treatment of NAFLD, and provide new ideas for prevention and treatment of NAFLD.

非酒精性脂肪肝（NAFLD）已成为全球性的公共健康问题，迄今为止其发病机制尚未阐明，亦没有理想的治疗药物。最新研究表明BNip3介导的线粒体自噬（mitophagy）异常能够导致肝脏脂质代谢紊乱，但其细胞内信号转导机制仍未清楚。本课题组前期研究发现木通皂苷D能够激活BNip3，提高自噬水平、保护线粒体，降低肝脏脂质沉积。由此推测木通皂苷D抗NAFLD的作用可能是通过调控BNip3-mitophagy相关通路实现的。本研究拟采用油酸诱导肝细胞脂质沉积及ob/ob小鼠为模型，研究干预BNip3及其上游AMPK、PI3K/AKT信号通路对线粒体自噬的影响，探讨木通皂苷D是否通过激活BNip3-mitophagy通路而实现调控NAFLD肝脏脂质代谢紊乱的作用，阐明其信号转导机制，为开发针对BNip3-mitophagy通路的药物提供新的思路，也为木通皂苷D的临床应用提供理论和实验依据。

随着人们生活水平的提高、饮食结构的改变及生活方式的变化，非酒精性脂肪肝（NAFLD）的发病率不断上升并呈年轻化趋势。流行病学研究显示，成人NAFLD的患病率为20-30%，而肥胖人群中NAFLD患病率高达80-90%，NAFLD已成为全球性的公共健康问题。迄今NAFLD的发病机制尚未完全明确，临床缺乏安全有效的治疗药物，因此，探讨明确NAFLD的防控机制，发现新型高效安全的治疗药物迫在眉睫。最新研究表明BNip3介导的线粒体自噬（mitophagy）异常能够导致肝脏脂质代谢紊乱，但其细胞内信号转导机制仍未清楚。以BNip3-mitophagy为靶点，为NAFLD的防治寻找新的药物很有必要。本研究采用油酸诱导肝细胞脂质沉积，发现木通皂苷D能够降低油酸引起的肝脏脂质沉积，能够升高BNip3的表达，增强线粒体自噬，干预BNip3药物效果不佳。以ob/ob小鼠为模型，发现木通皂苷D具有减少肝脏脂质沉积、增强自噬的作用，其作用与BNip3相关。本研究为开发针对BNip3-mitophagy通路的药物提供新的思路，也为木通皂苷D的临床应用提供理论和实验依据。