miR-218和miR-23a簇协同介导RNA编辑酶ADAR1对肝细胞脂肪代谢的调控机制研究

ADAR1 is a member of RNA editing enzyme family that involves in many physiological and pathological process. Our previous study showed that the expression of ADAR1 in hepatocyte was significant increased after oleic acid stimulation and adipose synthesis was prevented by upregulation of ADAR1. A set of miRNAs including miR-218 were found to be downregulated in ADAR1 upregulation cells. miRNA array showed that high expression of ADAR1 led to the remarkable upregulation of miRNAs including miRNA-218 and downregulation of miR23a cluster. cDNA array and bioinformatics confirmed that PPARα and AMPK were the target gene of miR-218. Also, PPARγ is the potential target of miR-23a cluster. Thses findings indicated that ADAR1 might regulate lipid metabolism in hepatocyte by acting on ADAR1-miR-218-PPARα,AMPK pathway and ADAR1-miR-23a culster-PPARγ pathway synergistically. The present study aims to investigate the synergistic molecular mechanisms of miR-218 and miR-23a culster involving in the ADAR1's modulation in lipid metabolism in hepatocyte. This novel mechanism of lipid metabolism in hepatocyte may provide new strategies and potential target for the treatment on fatty liver.

ADAR1是RNA编辑酶家族成员，参与了胚胎发育、机体免疫等重要的病理生理过程。课题组前期发现油酸刺激肝细胞后ADAR1表达升高，抑制了肝细胞脂肪合成。miRNA芯片筛选发现在ADAR1高表达肝细胞中一组包括miR-218在内的miRNAs显著下调，一组包括miR-23a 簇在内的miRNAs显著上调。进一步结合cDNA芯片、生物信息学分析并验证发现PPARα、AMPK是miR-218的潜在靶基因，PPARγ是miR-23a簇的潜在靶基因。我们推测ADAR1- miR-218-PPARα、AMPK和ADAR1-miR-23a 簇-PPARγ的协同调控可能在肝细胞脂肪代谢中发挥着重要作用。本研究拟通过常规的细胞分子生物学手段及代谢相关实验方法，揭示ADAR1通过调控miRNA表达参与肝细胞脂肪代谢的新机制。

ADAR1是RNA编辑酶家族成员之一，参与了胚胎发育、机体免疫等重要的病理生理过程。课题组前期发现油酸刺激肝细胞后ADAR1表达升高，从而抑制肝细胞脂肪合成。miRNA芯片筛选发现miR-218在ADAR1高表达肝细胞中显著下调，miR-23b 簇显著上调。进一步结合cDNA芯片、生物信息学分析及预实验发现PPARα1、AMPK是miR-218的潜在靶基因，PPARγ是miR-23b 簇的潜在靶基因。由此推测，ADAR1- miR-218-PPARα、AMPK通路和ADAR1-miR-23a 簇-PPARγ通路的协同调控可能在肝细胞的脂肪代谢中发挥了重要作用。通过本研究我们发现ADAR1对肝细胞脂肪代谢的调控是由miR-218和miR-23a簇介导的，证实ADAR1是通过ADAR1- miR-218-PPARα,AMPK和ADAR1-miR-23a簇-PPARγ通路来完成的，且在ADAR1高表达的肝细胞中miR-218和miR-23a簇存在“1+1>2”的协同调控作用，这一发现揭示了RNA编辑酶ADAR1通过调控miRNA分子的表达参与调控肝细胞脂肪代谢的新机制，是对miRNA分子参与肝细胞脂肪代谢调控机制的重要补充，并为抑制脂肪肝提供新的思路和潜在的治疗靶点。