FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB
FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB
复制标题
FXR 介导的 GLP-1R 表达表观遗传调控有助于增强 RYGB 后糖尿病患者肠促胰岛素的作用
DOI：
10.1111/jcmm.16339
复制
发表时间：
2021-02-21
影响因子：
5.3
通讯作者：
Ma, Xiaosong
中科院分区：
文献类型：
--
作者：
Kong, Xiangchen;Feng, Linxian;Ma, Xiaosong
在本研究中，我们研究了Roux-en-Y胃旁路(RYGB)如何增强GK大鼠胰高血糖素样肽1(GLP-1)的反应，并探讨了RYGB刺激的BAS/FXR信号与调节葡萄糖刺激的胰岛素分泌(GSIS)的关键途径--β细胞中GLP-1R相关信号之间的潜在联系。在这里，我们证明了RYGB恢复GK大鼠胰岛GLP-1R的表达。这涉及到总BAs和鹅去氧胆酸(CDCA)的增加，导致FXR激活，增加FXR与GLP-1R启动子的结合，增加组蛋白乙酰转移酶类固醇受体共激活因子-1(SRC1)的占有率，从而增加组蛋白H3在启动子上的乙酰化。这些协调的事件导致GLP-1R表达增加，导致β细胞对GLP-1的反应更强。此外，消融FXR可抑制GLP-1的刺激作用。因此，本研究揭示了BAS/FXR/SRC1轴调控的GLP-1R在胰岛β细胞中的表达，从而导致RYGB后GK大鼠胰岛素效应增强和血糖正常化。
In this study, we investigated how Roux-en-Y gastric bypass (RYGB) enhances glucagon-like peptide 1 (GLP-1) response in GK rats and explored the potential link between RYGB-stimulated BAs/FXR signalling and GLP-1R-linked signalling in beta-cells, a key pathway that regulates glucose-stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP-1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp-1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator-1 (SRC1), thus increasing histone H3 acetylation at the promoter. These coordinated events bring about increased GLP-1R expression, resulting in greater GLP-1 response in beta-cells. Moreover, ablation of FXR suppressed the stimulatory effects of GLP-1. Thus, this study unravels the crucial role of the BAs/FXR/SRC1 axis-controlled GLP-1R expression in beta-cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB.