Open AccessA novel role for farnesoid X receptor in the bile acid‐mediated intestinal glucose homeostasis
Author(s) -
Zhao Long,
Xuan Zefeng,
Song Wenfeng,
Zhang Shiyu,
Li Zequn,
Song Guangyuan,
Zhu Xingxin,
Xie Haiyang,
Zheng Shusen,
Song Penghong
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15881
Subject(s) - farnesoid x receptor , glut2 , glucose homeostasis , bile acid , medicine , homeostasis , endocrinology , chemistry , intestinal epithelium , glucose transporter , biology , biochemistry , nuclear receptor , diabetes mellitus , epithelium , insulin , insulin resistance , transcription factor , genetics , gene
The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA‐mediated glucose homeostasis in the intestine. BA‐activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA‐activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD‐related hyperglycaemia.