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

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机构: [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
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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. Copyright © 2020 Elsevier Inc. All rights reserved.

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出版当年[2021]版:
大类 | 1 区 生物学
小类 | 1 区 细胞生物学 1 区 内分泌学与代谢
最新[2023]版:
大类 | 1 区 生物学
小类 | 1 区 细胞生物学 1 区 内分泌学与代谢
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第一作者机构: [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
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通讯机构: [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 [7]University of Hawaii Cancer Center, Honolulu, HI 96813, USA [8]School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
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