反义lncRNA-AS-nnmt-plzf调控NNMT和PLZF基因转录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。作为一种lncRNA，反义lncRNA的功能尚不清楚。我们发现，肝脏反义lncRNA AS-nnmt-plzf的升高伴随甘油三酯蓄积及其代谢相关基因表达上调，RIP的结果表明AS-nnmt-plzf可与多梳蛋白Bmi-1结合，生物信息学预测AS-nnmt-plzf可靶向NNMT和PLZF。据此提出假说：AS-nnmt-plzf招募Bmi-1，抑制NNMT/PLZF转录，调控甘油三酯合成与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。本课题拟从分子、细胞、组织以及动物等多层次明确AS-nnmt-plzf在脂代谢紊乱中的作用；确定AS-nnmt-plzf对甘油三酯代谢相关基因的调控；揭示AS-nnmt-plzf介导肝脏甘油三酯蓄积的机制。从反义lncRNA 这个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. As a kind of lncRNA, the function of antisense lncRNA is poorly understood. In our preliminary study, we found that enhanced antisense lncRNA As-nnmt-plzf level was accompanied by the accumulation of hepatic triglyceride and up-regulation of lipid metabolism-related genes. RIP assay demonstrated that AS-nnmt-plzf could bind Polycomb protein Bmi-1 and Bioinformatic analysis predicted that AS-nnmt-plzf directly interacts with NNMT and PLZF. At present, no study has been conducted on the functional role of AS-nnmt-plzf. Here, we propose that AS-nnmt-plzf may function as a scaffold for Bmi-1 to inhibit the transcription of NNMT/PLZF, thereby regulating triglyceride metabolism-related gene expression. This project aim to evaluate the potential role of AS-nnmt-plzf in hepatic triglyceride metabolism disorder. We try to determine the regulation of AS-nnmt-plzf in triglyceride metabolism related genes and reveal the mechanism of AS-nnmt-plzf mediating hepatic triglyceride accumulation. We will provide novel insight for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) from the viewpoint of antisense lncRNA.