FXR‐mediated epigenetic regulation of GLP‐1R expression contributes to enhanced incretin effect in diabetes after RYGB
Xiangchen Kong, Linxian Feng, Dan Yan, Bingfeng Li, Yanhui Yang, Xiaosong Ma
Abstract
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 β-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 β-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 β-cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB.