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

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 LanCynthia Rajani, Guoxiang Xie, Aiping LYU, Weiping Jia*, Changtao Jiang, Wei JIA

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)791-803.e7
JournalCell Metabolism
Volume33
Issue number4
DOIs
Publication statusPublished - 6 Apr 2021

Scopus Subject Areas

  • Physiology
  • Molecular Biology
  • Cell Biology

User-Defined Keywords

  • bile acid
  • diabetes
  • FXR
  • glucagon-like peptide-1
  • glucose homeostasis
  • hyocholic acid
  • hyodeoxycholic acid
  • insulin
  • pig
  • TGR5

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