DUSP1/Bnip3/线粒体自噬信号通路拮抗线粒体分裂改善非酒精性脂肪性肝病的机制研究

高脂诱发线粒体分裂进而造成肝细胞代谢失调被认为是非酒精性脂肪性肝病（Nonalcohol fatty liver disease, NAFLD）核心发病机制。我们前期工作证实Bnip3介导的线粒体自噬改善线粒体氧化应激和生物代谢，由此减轻NAFLD进展。但Bnip3介导的线粒体自噬能否通过拮抗线粒体分裂、减少线粒体碎片的形成调节NAFLD进程尚缺乏相应证据。本课题组在心脏再灌注损伤模型中发现DUSP1是线粒体自噬和分裂的共同上游信号，但仍不清楚其能否改善高脂状态下Bnip3线粒体自噬活性而减轻线粒体分裂诱导的肝细胞损伤。本项目利用转基因鼠、蛋白敲低和过表达等技术，阐明高脂状态下DUSP1激活Bnip3线粒体自噬抑制线粒体分裂，维持线粒体的质量和数量，减轻高脂诱导肝损伤的分子机制。以线粒体结构和功能调控为中心，解决线粒体自噬和分裂之间的因果关系和交互逻辑，为改善NAFLD提供了新的分子靶点。

High-fat-mediated mitochondrial fission and subsequent liver cell metabolism disorders are considered to be the core pathogenesis of nonalcohol fatty liver disease (NAFLD). Our previous work confirmed that Bnip3-related mitophagy alleviates mitochondrial oxidative stress and improves biological metabolism, thereby slowing NAFLD progression. However, there is no relevant evidence to show whether Bnip3-related mitophagy can affect the process of NAFLD by antagonizing mitochondrial fission and reducing the formation of mitochondrial fragments. Our group found that DUSP1 is a common upstream signal of mitophagy and mitochondrial fission in the cardiac ischemia-reperfusion injury model, but it remains unclear whether it can improve Bnip3-related mitophagy activity under high-fat conditions and reduce mitochondrial fission-induced hepatocyte damage. In this current study, transgenic mice, loss- and gain-of-function assays would be performed to elucidate the molecular mechanism that DUSP1 activates Bnip3-related mitophagy, antagonizes mitochondrial fission and maintains mitochondrial quality and quantity to attenuate high-fat-mediated liver damage. Focusing on mitochondrial structure and function regulation, our study would decipher the causality and interaction relationship between mitophagy and mitochondrial fission, and provide experimental evidence and therapeutic targets for conferring protection against NAFLD damage.