贾伟 姜长涛 贾伟平：猪为何不得糖尿病？一类特殊的胆汁酸能强力控糖 | 热心肠日报

Cell Metabolism

[IF:21.567]

Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism

猪胆酸类通过一种独特的TGR5和FXR信号机制改善葡萄糖稳态

10.1016/j.cmet.2020.11.017

12-17, Article

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Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.

First Authors:
Xiaojiao Zheng,Tianlu Chen,Runqiu Jiang,Aihua Zhao

Correspondence Authors:
Weiping Jia,Changtao Jiang,Wei Jia

All Authors:
Xiaojiao Zheng,Tianlu Chen,Runqiu Jiang,Aihua Zhao,Qing Wu,Junliang Kuang,Dongnan Sun,Zhenxing Ren,Mengci Li,Mingliang Zhao,Shouli Wang,Yuqian Bao,Huating Li,Cheng Hu,Bing Dong,Defa Li,Jiayu Wu,Jialin Xia,Xuemei Wang,Ke Lan,Cynthia Rajani,Guoxiang Xie,Aiping Lu,Weiping Jia,Changtao Jiang,Wei Jia