α/β水解酶结构域-6(ABHD6)近来被认为是治疗糖尿病等代谢性疾病的新靶点,但其对肝脏糖、脂代谢的调控作用未明。本研究目的为明确ABHD6对肝脏糖、脂代谢的调控作用及机制。前期在ABHD6敲除及过表达肝细胞中发现，ABHD6与肝细胞糖、脂代谢密切相关,其机制与调节PTP1B表达、影响胰岛素敏感性及内质网应激有关。接下来,拟建立ABHD6肝脏组织特异敲除小鼠(ABHD6-cKO小鼠)，监测糖代谢、NAFLD进展程度、胰岛素敏感性等指标，进一步明确ABHD6在肝脏糖、脂代谢中的作用。在细胞/动物组织中进一步探讨其机制，包括ABHD6对PTP1B的具体调节机制,并采用转录组/蛋白组学分析其参与糖代谢的机制;脂质组学分析肝脏中ABHD6的底物,寻找其可能的配体,探索其参与肝脏脂质代谢的新机制。本研究将为NAFLD及代谢综合征药物研发提供新的靶点和思路。

The α/β hydrolase domain-6 (ABHD6) has recently been considered as a new target for the treatment of metabolic diseases such as diabetes, but its regulation of hepatic glucose and lipid metabolism is unknown. The aim of this study is to clarify the regulatory effect and mechanism of ABHD6 on hepatic glucose and lipid metabolism. Our previous work found that the expression of ABHD6 was closely related to the metabolism of glucose and lipid in hepatocytes: the glucose output was down-regulated in ABHD6 knockout hepatocytes, and the TG level was also decreased; ABHD6 overexpression increased the glucose output of hepatocytes, and significantly increased the level of TG. Its mechanism was related to regulating PTP1B expression, affecting insulin sensitivity and endoplasmic reticulum stress. In this study, to further explore the role of ABHD6 in hepatic glucose and lipid metabolism, ABHD6 liver tissue specific knockout mice (ABHD6-cKO mice) will be established, the glucose metabolism, NAFLD progression, and insulin sensitivity will be evaluated, respectively. The mechanism will be further explored in hepatocyte/liver tissues, including the specific regulatory mechanism of ABHD6 on PTP1B expression. Lipidomics will be conducted to analyze the substrate of ABHD6, and find the possible ligands of the substrate in liver. Transcriptome/proteomics will be performed to analyze the new mechanism of its involvement in glycometabolism and lipid metabolism. This study will provide new targets and ideas for drug research and development of NAFLD and metabolic syndrome.