The role of bile acids in physiology and pathophysiology of pancreatic beta-cells

胆汁酸(BA)除了在脂质代谢中发挥重要作用外，还参与调节葡萄糖的动态平衡。在这个项目中，将阐明影响内分泌胰腺功能的机制。我的团队最近的工作表明，核法尼醇X受体(FXR)在β细胞中表达，刺激该受体可以增加胰岛素的分泌。由于BA对刺激-分泌偶联(SSC)的不同参数的影响发生在几分钟内，本项目的目的之一是评估BA的哪些效应是通过基因组激活介导的，哪些是通过其他信号途径发生的。在此背景下，将研究FXR在什么条件下位于胞浆或细胞核中，并将研究受体易位的功能后果。我们以前的工作表明，FXR调节KATP通道的活动。因此，研究构成FXR和KATP通道之间联系的分子机制(S)是另一个目标。在体内，我们将解决这样一个问题，即通过喂养不同的饲料(添加BAS或BA结合树脂)实现的BA池的变化如何改变糖尿病前期小鼠与对照组动物的葡萄糖稳态。体外实验有望发现BAS作用方式的分子机制。此外，预计体内实验有助于了解如何将BA池用作治疗干预的靶点。

Bile acids (BAs) are -besides their important role in lipid metabolism- involved in the regulation of glucose homeostasis. In this project it will be clarified by which mechanisms BAs influence the function of the endocrine pancreas. Recent work of my group demonstrated that the nuclear farnesoid X receptor (FXR) is expressed in beta-cells and that stimulation of this receptor augments insulin secretion. Since the effects of BAs on different parameters of stimulus-secretion coupling (SSC) occurred within minutes, it is one aim of this project to evaluate which of the BA effects are mediated by genome activation and which occur via other signaling pathways. In this context it will be investigated under which conditions the FXR is located in the cytosol or in the nucleus and functional consequences of the receptor translocation will be studied. Our previous work showed that FXR modulates the activity of KATP channels. Therefore it is another goal to detect the molecular mechanism(s) that constitute the link between FXR and KATP channels. In vivo we will address the question how changes in the BA pool achieved by feeding of different diets (addition of BAs or BA-binding resins) alter glucose homeostasis in prediabetic mice vs. control animals. It is expected that in vitro experiments will discover molecular mechanisms involved in the mode of action of BAs. Moreover, it is anticipated that the in vivo experiments contribute to the knowledge how the BA pool can be used as a target for therapeutic intervention.