肝脏ZNRF3对机体能量代谢的影响和作用机制研究

肝脏是机体物质代谢的中心，也是治疗代谢性疾病的重要靶器官。前期研究工作发现，ZNRF3在肥胖病人和肥胖小鼠的肝脏表达显著升高。肝脏ZNRF3及其同源物RNF43基因双敲除小鼠肝脏脂质沉积减少，胰岛素敏感性增加，与对照相比，敲除组小鼠体重明显减轻，体脂变少，体温升高，代谢监测实验显示基础代谢率增加，且白色脂肪组织呈现棕色化的倾向。在本课题中，我们将首次建立肝脏时空特异性ZNRF3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ZNRF3在肝脏糖脂代谢及全身能量平衡中的调控作用，对深入认识ZNRF3的生物学功能至关重要，也为预防和治疗代谢性疾病提供更多的参考和理论依据。

Liver is the center of metabolism and the key target organ for metabolic diseases. ZNRF3 is a key molecule of the WNT signaling pathway recently. Previous study have found the increased liver ZNRF3 expression in obese patients and obese mice. Specific liver ZNRF3 and its homologous gene RNF43 double knockout decreases mice lipid deposition and increases insulin sensitivity. More importantly, compared with the control mice, the double knockout mice display significantly reduced body weight, decreased body fat, increased body temperature, increased basal metabolic rate, and browning tendency in adipose tissue. In this project, we will establish liver spatiotemporally specific ZNRF3 knockout mice model for the first time, and demonstrate the significant role and underlying mechanism of ZNRF3 in regulating hepatic glucose and lipid metabolism and systemic energy metabolism in vivo and in vitro by using modern cell biological and molecular biological methods. It will be of importance to reveal further the biological function of ZNRF3 and to provide a novel strategy in preventing and treating metabolic disease theoretically and practically.