2. Academic Validation
  3. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism

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

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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