β-Klotho (KLB)是在脂肪和肝脏高表达的跨膜蛋白，其在脂肪细胞可作为FGF21及FGF19维持糖脂代谢稳态的共同受体。但目前KLB在调节肝脏糖脂代谢中的功能及机理尚不明确。本课题组前期研究结果显示，FGF21可显著改善小鼠肝内脂肪蓄积及胰岛素抵抗；KLB肝脏表达水平在高脂饮食诱导的肥胖小鼠模型中显著下调。基于上述前期研究结果，本课题研究假设是：KLB对于维持肝脏糖脂代谢稳态发挥重要功能，是介导FGF21及FGF19糖脂代谢调节功能的核心分子。为验证该假设，本项目将利用Cre-lox重组系统产生肝脏特异性KLB敲除小鼠及AAV系统介导KLB肝脏过表达的实验设计；同时，采用肝特异性KLB敲除小鼠结合重组FGF21及FGF19持续灌注的研究策略。研究结果对于揭肝脏特异性KLB在肝脏及全身糖脂代谢，及其在介导FGF21及FGF19的糖脂代谢调节中发挥的功能及机制具有重要科学意义。

β-Klotho (KLB) is a single-pass transmembrane protein with relatively high abundance in adipose tissue and the liver. In adipose tissue, KLB acts as adaptor protein for FGF receptors to form cell surface receptor complexes, thereby mediating the regulatory effects of FGF21 and FGF19 on the maintenance of metabolic homeostasis. However, the role of hepatocyte-specific KLB on lipid metabolism in the liver and circulating lipid profile has not been explored so far. Previous reports from our group demonstrated that chronic administration of recombinant mouse FGF21 protein exerts protective effects on high fat diet-induced hepatic steatosis and insulin resistance in mice. In light of these previous findings, the research hypothesis of the present project is that hepatocyte-specific KLB plays a crucial role in regulating lipid metabolism. Additionally, it functions as a key mediator for the regulatory role of FGF21 and FGF19 on lipid metabolism in the liver and circulating lipid profile. To test this hypothesis, we employed comprehensive phenotyping strategy in liver-specific KLB knockout mice generated through Cre-Lox recombination technology and mice with adeno-associated virus-mediated KLB overexpression in the liver. In addition, liver-specific KLB knockout mice will be chronically infused with either recombinant FGF21 or FGF19 proteins. The findings in this project will be of significant importance to delineate the potential role(s) of hepatocyte-specific KLB in the regulation of lipid metabolism in the liver and in mediating of metabolic regulatory effect of FGF21 and FGF19.