锌指蛋白ZNF638调控肝脏糖异生的作用和机制研究

2型糖尿病严重威胁人类健康。肝脏糖异生异常激活是造成高血糖和糖尿病的重要原因，然而其调控机制和可干预靶点尚不清晰。本项目前期鉴定出糖异生转录复合物新组分锌指蛋白成员ZNF638。初步发现ZNF638在饥饿和胰岛素抵抗状态下表达升高，并受CREB转录调控。ZNF638肝脏特异性敲除小鼠空腹血糖降低，糖异生下降，并改善高脂饮食引起的胰岛素抵抗；而腺病毒介导的ZNF638肝脏过表达能够显著提高小鼠肝脏糖异生和空腹血糖。机制研究显示ZNF638可能通过与PGC1ɑ以及CREB结合，协同促进糖异生基因Pepck等转录激活。基于以上发现，本项目将以ZNF638肝脏特异性敲除和过表达小鼠为主要研究模型，借助原代肝细胞分离技术，以及细胞和分子生物学技术平台，阐明ZNF638调控肝脏糖异生和机体糖代谢稳态的分子机制，为治疗2型糖尿病提供新的分子靶点和理论基础。

Type 2 diabetes is one of the leading chronic metabolic diseases world-widely. Increased hepatic glucose production caused by abnormally activated hepatic gluconeogenesis contributes to hyperglycemia and diabetes. Recently, we identified a novel component of gluconeogenic transcriptional complex, Zinc finger protein ZNF638. Preliminary data showed that Znf638 mRNA levels were increased under fasting and diabetic conditions and was transcriptionally activated by CREB. ZNF638 liver conditional knockout mice showed decreased glucose levels and gluconeogenic capability, as well as improved insulin sensitivity under diabetic conditions. Conversely, ZNF638 overexpression in liver via adenovirus delivery increased gluconeogenesis. Gene expression analysis revealed that Pecpk and G6pase was under the control of ZNF638 and detailed mechanistic studies suggested that ZNF638 cooperated with PGC1ɑ and CREB for transcriptional activation of Pepck. Based on these results, we will further elucidate the role and mechanism of ZNF638 in the regulation of hepatic gluconeogenesis using established animal models. Overall, our work would provide novel therapeutic targets and potential molecular basis for combating type 2 diabetes.