LGR4/GPR48对肝脏糖脂代谢的调控作用及机制研究

肝脏糖脂代谢紊乱是导致胰岛素抵抗以至2型糖尿病的一个重要推动因素。LGR4/GPR48属于G 蛋白偶联受体家族。前期工作发现，LGR4表达受营养状况的影响，其在几种经典的胰岛素抵抗和2型糖尿病小鼠肝脏中表达都显著升高。LGR4全身基因敲除小鼠胰岛素抵抗改善明显，肝脏糖脂代谢紊乱得到纠正，肝脏差异表达基因的信号通路分析显示代谢途径改善最显著。高脂和db/db小鼠通过腺病毒在肝脏干扰LGR4的表达后，肝脏糖脂代谢显著改善，全身胰岛素敏感性增加，肝糖异生减少。本课题中我们将首次建立肝脏组织特异性LGR4敲除小鼠，从体内和体外水平，结合细胞生物学和分子生物学技术，详细探究LGR4在肝脏糖脂代谢中的调控作用，阐明其在肝脏及全身胰岛素抵抗中的角色，对更深入认识LGR4的生物学功能至关重要，为预防和治疗代谢性疾病提供理论依据。G 蛋白偶联受体一直是药物筛选的热点，因此对治疗糖尿病药物的开发亦具指导意义。

Disregulation of glucose and lipid metabolism in liver can lead to insulin resistance and even type 2 diabetes. Leucine-rich-repeat-containing G-protein-coupled Receptor 4 (LGR4, also GRP48) belongs to a member of G protein coupled receptor family. We have found increased LGR4 mRNA expression in insulin resistant and diabtetic mice, such as high fat diet (HFD)-fed mice, ob/ob and db/db mice confirmed by quantitative realtime RT-PCR. LGR4 whole body knockout mice display more insulin sensitive condition when compared with wild type mice, disordered hepatic glucose and lipid metabolism were corrected. Pathway analysis of Micro-array results showed that metabolic pathway was mostly changed. Our preliminary results also demonstrated that knockdown of LGR4 in liver by adenovirus improved the insulin resistance in db/db mice and HFD-fed mice, the gluconeogenesis decreased and disordered hepatic glucose and lipid metabolism were significantly corrected. In this project, we will establish liver specific LGR4 knockout mouse model for the first time, which is in process. By using this mouse model, in the present study, we will demonstrate the significant role and underlying mechanism of LGR4 in regulating hepatic glucose and lipid metabolism in vivo and in vitro by using modern cell biological and molecular biological methods. We will also elucidated the role of LGR4 in the local and system insulin resistance. It will be of importance to reveal further the biological function of LGR4 and to provide a novel strategy in preventing and treating metabolic disease theoretically and practically. It should be noted that G protein coupled receptors are always the focus in drug development which makes our project be of great instructional value.