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

  • Cell Metab. 2021 Apr 6;33(4):791-803.e7. doi: 10.1016/j.cmet.2020.11.017.
Xiaojiao Zheng  1 ,  Tianlu Chen  1 ,  Runqiu Jiang  2 ,  Aihua Zhao  1 ,  Qing Wu  3 ,  Junliang Kuang  1 ,  Dongnan Sun  1 ,  Zhenxing Ren  1 ,  Mengci Li  1 ,  Mingliang Zhao  1 ,  Shouli Wang  1 ,  Yuqian Bao  4 ,  Huating Li  4 ,  Cheng Hu  4 ,  Bing Dong  5 ,  Defa Li  5 ,  Jiayu Wu  3 ,  Jialin Xia  3 ,  Xuemei Wang  3 ,  Ke Lan  6 ,  Cynthia Rajani  7 ,  Guoxiang Xie  7 ,  Aiping Lu  8 ,  Weiping Jia  9 ,  Changtao Jiang  10 ,  Wei Jia  11
Affiliations
  • 1. Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
  • 2. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, China.
  • 3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
  • 4. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai 200233, China.
  • 5. National Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China.
  • 6. Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 7. University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
  • 8. School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
  • 9. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai 200233, China. Electronic address: [email protected].
  • 10. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: [email protected].
  • 11. Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA; School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: [email protected].
PMID: 33338411 DOI: 10.1016/j.cmet.2020.11.017
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.

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