FGF19在肝脏胰岛素抵抗中的作用和机制

Bile acids are the end product of cholesterol catabolism. Bile acids are not only involved in facilitating gut nutrient absorption, but also in controlling the metabolism of glucose and lipid through the enterohepatic circulation of bile acids. Fibroblast growth factor FGF19 is an enterohapatic hormone induced by bile acids and secreted by intestine. It is reported that FGF19 mediates the feedback regulation of bile acids, suggesting the possible role of FGF19 in glucose and lipids metabolism in liver. It is still not clear that the role of FGF19 plays in tissues. In the previous study, we have observed the key role of PGC-1(PPAR-gamma receptor coactivator 1) in hepatic lipid and glucose metabolism. In the present study, we will focus on the effect of FGF19 on fatty acid metabolism and gluconeogenesis in liver, and its effect on lipolysis and secretion of incretin GLP-1,by using insulin resistance animal and cell culture. RT-PCR and cell cotransfection method will be applied for this study. We will provide the evidence of improving insulin resistance by FGF19,and the potentials of developing novel therapeutic strategies that target bile acid metabolism for treatment of diabetes mellitus and metabolic syndrome.

胆汁酸是胆固醇分解代谢的终产物。胆汁酸通过肠肝循环参与脂类物质的吸收和糖脂代谢的调节。成纤维细胞生长因子FGF19是一种胆汁酸刺激由肠道细胞分泌的肝肠激素，最近的研究证实FGF19参与了胆汁酸肠肝循环的调控，因此，我们推测FGF19在肝脏的糖脂代谢调节中发挥重要作用。目前，FGF19的作用及机制尚未完全清楚。在前期研究中，我们证实了核受体辅激活因子PGC-1在肝脏糖脂代谢调节中具有关键作用。本项研究以胰岛素抵抗动物模型和细胞培养为基础，应用RT-PCR、细胞转染等分子生物学技术观察FGF19对脂肪酸氧化、糖异生和脂肪分解的影响，以及与PGC-1信号通路间的关系，观察FGF19 对肠促激素GLP-1分泌的影响。本课题将揭示FGF19改善胰岛素抵抗的作用机制，并以胆汁酸代谢为靶点为糖尿病和代谢综合征的防治提供新方向。

肝脏脂肪的异常沉积和胰岛素抵抗是引起糖尿病和代谢综合征的重要原因。成纤维细胞生长因子FGF19是一种由肠道细胞分泌的肝肠激素。FGF19不仅参与维持胆汁酸代谢的平衡，而且在糖脂代谢调节中发挥重要作用。在本项研究中，无论在体外细胞实验和动物实验中，均显示了FGF19能够抑制糖异生、促进脂肪酸氧化、改善糖代谢异常，以及在动物实验中能够减少肝脏内脂质沉积。分子生物学实验的结果证实FGF19能够上调PGC-1a，通过PI3K信号通路调节葡萄糖代谢。此外，在研究中我们观察了FGF19对肠道菌群的影响。本课题的研究结果揭示了FGF19改善胰岛素抵抗的作用及可能的分子机制，并为糖尿病和代谢综合征的防治提供新的靶点。