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

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 Lu, Weiping Jia^*, Changtao Jiang^*, Wei Jia^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

266 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 language	English
Pages (from-to)	791-803.E7
Number of pages	20
Journal	Cell Metabolism
Volume	33
Issue number	4
Early online date	17 Dec 2020
DOIs	https://doi.org/10.1016/j.cmet.2020.11.017
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2020.11.017

Cite this

Zheng, X., Chen, T., Jiang, R., Zhao, A., Wu, Q., Kuang, J., Sun, D., Ren, Z., Li, M., Zhao, M., Wang, S., Bao, Y., Li, H., Hu, C., Dong, B., Li, D., Wu, J., Xia, J., Wang, X., ... Jia, W. (2021). Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metabolism, 33(4), 791-803.E7. https://doi.org/10.1016/j.cmet.2020.11.017

@article{177ef2c96b8841caa6b624e57a1265c9,

title = "Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism",

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

author = "Xiaojiao Zheng and Tianlu Chen and Runqiu Jiang and Aihua Zhao and Qing Wu and Junliang Kuang and Dongnan Sun and Zhenxing Ren and Mengci Li and Mingliang Zhao and Shouli Wang and Yuqian Bao and Huating Li and Cheng Hu and Bing Dong and Defa Li and Jiayu Wu and Jialin Xia and Xuemei Wang and Ke Lan and Cynthia Rajani and Guoxiang Xie and Aiping Lu and Weiping Jia and Changtao Jiang and Wei Jia",

note = "Funding Information: This work was supported by the National Natural Science Foundation of China (81974073, 81772530, 31972935, and 91857115), and National Key R&D Program of China (2019YFA0802300). We thank Yulong Li (State Key Laboratory of Membrane Biology, Peking University School of Life Sciences) for their TGR5 luciferase reporter stable cell line during luciferase assays. Publisher copyright: {\textcopyright} 2020 Elsevier Inc. ",

year = "2021",

month = apr,

day = "6",

doi = "10.1016/j.cmet.2020.11.017",

language = "English",

volume = "33",

pages = "791--803.E7",

journal = "Cell Metabolism",

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publisher = "Cell Press",

number = "4",

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Zheng, X, Chen, T, Jiang, R, Zhao, A, Wu, Q, Kuang, J, Sun, D, Ren, Z, Li, M, Zhao, M, Wang, S, Bao, Y, Li, H, Hu, C, Dong, B, Li, D, Wu, J, Xia, J, Wang, X, Lan, K, Rajani, C, Xie, G, Lu, A, Jia, W, Jiang, C & Jia, W 2021, 'Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism', Cell Metabolism, vol. 33, no. 4, pp. 791-803.E7. https://doi.org/10.1016/j.cmet.2020.11.017

TY - JOUR

T1 - Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism

AU - Zheng, Xiaojiao

AU - Chen, Tianlu

AU - Jiang, Runqiu

AU - Zhao, Aihua

AU - Wu, Qing

AU - Kuang, Junliang

AU - Sun, Dongnan

AU - Ren, Zhenxing

AU - Li, Mengci

AU - Zhao, Mingliang

AU - Wang, Shouli

AU - Bao, Yuqian

AU - Li, Huating

AU - Hu, Cheng

AU - Dong, Bing

AU - Li, Defa

AU - Wu, Jiayu

AU - Xia, Jialin

AU - Wang, Xuemei

AU - Lan, Ke

AU - Rajani, Cynthia

AU - Xie, Guoxiang

AU - Lu, Aiping

AU - Jia, Weiping

AU - Jiang, Changtao

AU - Jia, Wei

N1 - Funding Information: This work was supported by the National Natural Science Foundation of China (81974073, 81772530, 31972935, and 91857115), and National Key R&D Program of China (2019YFA0802300). We thank Yulong Li (State Key Laboratory of Membrane Biology, Peking University School of Life Sciences) for their TGR5 luciferase reporter stable cell line during luciferase assays. Publisher copyright: © 2020 Elsevier Inc.

PY - 2021/4/6

Y1 - 2021/4/6

N2 - 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.

AB - 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.

KW - bile acid

KW - diabetes

KW - FXR

KW - glucagon-like peptide-1

KW - glucose homeostasis

KW - hyocholic acid

KW - hyodeoxycholic acid

KW - insulin

KW - pig

KW - TGR5

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U2 - 10.1016/j.cmet.2020.11.017

DO - 10.1016/j.cmet.2020.11.017

M3 - Journal article

C2 - 33338411

AN - SCOPUS:85099251673

SN - 1550-4131

VL - 33

SP - 791-803.E7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

Abstract

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