CREBH调控溶酶体酸化对肝细胞脂质自噬的影响及机制

自噬调节脂质代谢在非酒精性脂肪性肝病(NAFLD)发生发展过程中起重要作用，但是在脂质过载肝细胞中调控自噬有效清除脂质的机制尚不明确。我们课题组在前期工作中发现调控环磷酸腺苷反应元件结合蛋白H(CREBH)的表达可影响脂质过载肝细胞的自噬功能及脂滴含量。结合文献报道及生物信息学检测显示，CREBH极有可能通过调控空泡型质子泵三磷酸腺苷酶(V-H+-ATPase)复合体辅助亚基H+转运ATP酶溶酶体辅助蛋白2(ATP6AP2)的表达，调节溶酶体腔酸化功能，增强脂质自噬而降解脂质。因此，本项目拟采用靶基因过表达与沉默或敲除、双荧光素酶报告基因等技术及NAFLD细胞和动物模型，探讨并阐明CREBH通过转录调控ATP6AP2，促进溶酶体水解功能，增强脂质自噬，从而减少脂质沉积的作用及分子机制，为阻断NAFLD的发生发展提供新的理论和实验依据。

Autophagy plays a crucial role in the regulation of lipid metabolism in non-alcoholic fatty liver disease (NAFLD)；however, the mechanism of lipid degradation in lipid overload hepatocytes remains unclear. Our preliminary study showed that cyclic AMP-responsive element binding protein H (CREBH) expression improved autophagy system and lipid content. Furthermore, the literatures and bioinformatics prediction showed that CREBH might regulate ATPase H+ transporting lysosomal accessory protein 2(ATP6AP2) expression to regulate the lysosomal acidification and promote lipophagy. Therefore, in this research project，by using gene overexpression or knockdown or knockout,dual-luciferase reporter genes in NAFLD cell and mouse models, we will explore the roles and mechanisms that CREBH upregulates ATP6AP2 expression to promote lysosomal hydrolysis and lipophagy,which involved in lipid deposition. Our project may provide new theoretical and experimental basis for blocking the occurrence and progression of NAFLD.