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

胆汁酸在胰腺β细胞生理学和病理生理学中的作用

基本信息

批准号：
260646784
负责人：
Professorin Dr. Gisela Drews
金额：
--
依托单位：
Fachrichtung Pharmakologie, Toxikologie und Klinische Pharmazie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/260646784?language=en
关键词：
role bile acids physiology pathophysiology

项目摘要

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.

胆汁酸（BA）除了在脂质代谢中发挥重要作用外，还参与葡萄糖稳态的调节。在该项目中，将阐明 BA 通过哪些机制影响内分泌胰腺的功能。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，刺激该受体会增强胰岛素分泌。由于 BA 对刺激-分泌耦合 (SSC) 不同参数的影响在几分钟内发生，因此该项目的目的之一是评估哪些 BA 效应是由基因组激活介导的，哪些是通过其他信号通路发生的。在这种情况下，将研究 FXR 在何种条件下位于细胞质或细胞核中，并研究受体易位的功能后果。我们之前的工作表明 FXR 调节 KATP 通道的活性。因此，另一个目标是检测构成 FXR 和 KATP 通道之间联系的分子机制。在体内，我们将解决通过喂养不同饮食（添加 BA 或 BA 结合树脂）实现的 BA 池变化如何改变糖尿病前期小鼠与对照动物的葡萄糖稳态的问题。预计体外实验将发现涉及 BA 作用模式的分子机制。此外，预计体内实验有助于了解如何将 BA 库用作治疗干预的目标。