LncRNA-FAM225A-201调控GLS1转录后O-葡糖基化改变介导肝脏甘油三酯代谢紊乱的机制研究

LncRNA在肝脏脂代谢紊乱中起重要作用。目前，多数lncRNA的功能尚不清楚。 我们发现肝脏lncRNA FAM225A-201的升高伴随甘油三酯蓄积及脂质β氧化相关基因表达下调，RIP结果表明FAM225A-201可与O-GlcNAc糖基转移酶OGT结合，芯片共表达分析结果提示FAM225A-201与谷氨酰胺酶GLS1存在共表达关系。据此提出假说：FAM225A-201招募OGT，促进GLS1转录后O-葡糖基化修饰，调控氧化应激与β-氧化相关基因的表达，介导甘油三酯的异常蓄积。目前未见相关报道。本课题拟从多层次明确FAM225A-201在脂代谢紊乱中的作用；确定FAM225A-201对甘油三酯代谢相关基因的调控；揭示FAM225A-201介导肝脏甘油三酯蓄积的机制。从揭示lncRNA、糖基化修饰和氧化应激内在联系的新视点探讨肝脏脂代谢紊乱的发生机制，为非酒精性脂肪肝的防治提供新的思路。

Long non coding RNAs (lncRNAs) are suggested to play an important role in hepatic lipid metabolism disorder. At present, the function of most lncRNAs is poorly understood. In our preliminary study, we found that enhanced lncRNA FAM225A-201 level was accompanied by the accumulation of hepatic triglyceride and down-regulation of lipid β-oxidation-related genes. RIP assay demonstrated that FAM225A-201 could bind O-GlcNAc glycosyltransferase OGT and chip co-expression analysis suggested that FAM225A-201 has a co-expression relationship with glutaminase GLS1. At present, no study has been conducted on the functional role of FAM225A-201. Here, we propose that FAM225A-201 may function as a scaffold for OGT to promote GLS1 O-glucosylation modification after its transcription, thereby regulating triglyceride metabolism-related gene expression. This project aims to evaluate the potential role of FAM225A-201 in hepatic triglyceride metabolism disorder. We try to determine the regulation of FAM225A-201 in triglyceride metabolism related genes and reveal the mechanism of FAM225A-201 mediating hepatic triglyceride accumulation. We will provide novel insight for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) from the viewpoint of revealing the inner connection of lncRNA, glycosylation and oxidative stress.