Cyclophilin D介导的线粒体功能障碍诱导肝脏脂质沉积的分子机制及其在非酒精性脂肪性肝病发生发展的作用

The hepatic triglyceride (TG) accumulation is the innitial step of the development of non-alcoholic fatty liver disease (NAFLD). However, the mechanism of hepatic TG accumulation is still not clear. Mitochondrial dysfunction plays an important role in the development of NAFLD. Previous studies have paid more attention to the role of mitochondrial stress in "second hit" of NAFLD. Our previous study found that hepatic mitochondrial dysfunciton is earlier that TG accumulation in the high-fat diet fed mice, and cyclophilin D inhibitor improves hepatic TG accumilation induced by high-fat diet feeding. Based on these results, we propose that cyclophilin D-mediated mitochondrial dysfunction may be involved in hepatic TG accumulation in NAFLD. In this project, we will explore the molecular mechanism of mitochondrial dysfunciton in the development of NAFLD by using in vitro and in vivo methods at molecular, cellular and holistic levels. Furthermore, we will explore the protective effect of mitochondria stress inhbitor on NAFLD, which will provide a new strategy for clinical prevention and treatment of NAFLD.

甘油三酯（Triglyceride，TG）在肝脏的沉积是非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）发生发展的核心环节。但TG在肝脏沉积的内在机制尚不明确。线粒体功能障碍在NAFLD发生发展中发挥重要的作用。既往研究多关注线粒体应激在NAFLD发生的“二次打击”中的作用。申请人前期研究发现高脂饮食下肝脏线粒体应激先于TG沉积的发生，且体内应用CyclophilinD抑制剂可改善高脂饮食引起的肝脏TG沉积，因此我们提出CyclophilinD介导的线粒体应激可能参与了高脂饮食诱导的肝脏TG沉积。申请人将在前期研究的基础上，在分子、细胞和整体三个水平，采用体内、体外相结合的的的方法，探讨线粒体应激在NAFLD发生发展中的作用及分子机制，并进一步探讨线粒体应激保护剂对NAFLD的预防作用，为临床预防和治疗NAFLD提供新的策略。

甘油三酯（Triglyceride，TG）在肝脏的沉积是非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）发生发展的核心环节。但TG在肝脏沉积的内在机制尚不明确。线粒体功能障碍在NAFLD发生发展中发挥重要的作用。本课题组前期研究发现高脂饮食下肝脏线粒体应激先于TG沉积的发生，且体内应用CyclophilinD抑制剂可改善高脂饮食引起的肝脏TG沉积。本项目基于此，提出CyclophilinD介导的线粒体应激可能参与了高脂饮食诱导的肝脏TG沉积，并在分子、细胞和整体三个水平，采用体内、体外相结合的的方法，深入探讨了线粒体应激在NAFLD发生发展中的作用及分子机制。发现CypD表达升高可导致线粒体功能障碍，同时可通过抑制 PPARα/Cpt1α通路，提高脂质合成基因的转录水平，并降低脂质分解和利用基因表达。此外，CypD在抑制脂肪酸氧化的同时还会可提高ROS的产生，进一步提高了TNF-a和IL-6的转录水平，加重炎症状态。本项目的成果是对经典“二次打击”或者“多次打击”学说的重要补充，为NAFLD可能是一种线粒体疾病提供了新的实证依据。阐明了线粒体应激不仅仅是脂肪沉积的“果”，也可以是脂肪沉积的“因”，并且抑制CypD有望成为一种治疗早期NASH的新策略。