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 Lan; Cynthia Rajani; Guoxiang Xie; Aiping Lu; Weiping Jia; Changtao Jiang; Wei Jia

doi:10.1016/j.cmet.2020.11.017

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. Epub 2020 Dec 17.

Authors

Xiaojiao Zheng¹, Tianlu Chen¹, Runqiu Jiang², Aihua Zhao¹, Qing Wu³, Junliang Kuang¹, Dongnan Sun¹, Zhenxing Ren¹, Mengci Li¹, Mingliang Zhao¹, Shouli Wang¹, Yuqian Bao⁴, Huating Li⁴, Cheng Hu⁴, Bing Dong⁵, Defa Li⁵, Jiayu Wu³, Jialin Xia³, Xuemei Wang³, Ke Lan⁶, Cynthia Rajani⁷, Guoxiang Xie⁷, Aiping Lu⁸, Weiping Jia⁹, Changtao Jiang¹⁰, Wei Jia¹¹

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: wpjia@sjtu.edu.cn.
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: jiangchangtao@bjmu.edu.cn.
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: weijia1@hkbu.edu.hk.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / analysis
Cell Line
Cholic Acids / blood
Cholic Acids / chemistry
Cholic Acids / pharmacology
Cholic Acids / therapeutic use*
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Glucagon-Like Peptide 1 / metabolism
Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
Glucagon-Like Peptide-1 Receptor / metabolism
Glucose / metabolism*
Humans
Isoxazoles / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Cytoplasmic and Nuclear / metabolism*
Receptors, G-Protein-Coupled / deficiency
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction / drug effects
Swine

Substances

Blood Glucose
Cholic Acids
Glucagon-Like Peptide-1 Receptor
Isoxazoles
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled
farnesoid X-activated receptor
muricholic acid
Glucagon-Like Peptide 1
Glucose
GW 4064