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

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 pep...

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Published in:Cell metabolism Vol. 33; no. 4; p. 791
Main Authors: Zheng, Xiaojiao, Chen, Tianlu, Jiang, Runqiu, Zhao, Aihua, Wu, Qing, Kuang, Junliang, Sun, Dongnan, Ren, Zhenxing, Li, Mengci, Zhao, Mingliang, Wang, Shouli, Bao, Yuqian, Li, Huating, Hu, Cheng, Dong, Bing, Li, Defa, Wu, Jiayu, Xia, Jialin, Wang, Xuemei, Lan, Ke, Rajani, Cynthia, Xie, Guoxiang, Lu, Aiping, Jia, Weiping, Jiang, Changtao, Jia, Wei
Format: Journal Article
Language:English
Published: United States 06.04.2021
Subjects:
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
FXR
TGR5
glucose homeostasis
insulin
bile acid
glucagon-like peptide-1
hyodeoxycholic acid
hyocholic acid
diabetes
pig
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary: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.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2020.11.017