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

TitleHyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism
Authors
Keywordsbile acid
diabetes
FXR
glucagon-like peptide-1
glucose homeostasis
hyocholic acid
hyodeoxycholic acid
insulin
pig
TGR5
Issue Date2021
Citation
Cell Metabolism, 2021, v. 33, n. 4, p. 791-803.e7 How to Cite?
AbstractHyocholic 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.
Persistent Identifierhttp://hdl.handle.net/10722/342612
ISSN
2023 Impact Factor: 27.7
2023 SCImago Journal Rankings: 11.406
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZheng, Xiaojiao-
dc.contributor.authorChen, Tianlu-
dc.contributor.authorJiang, Runqiu-
dc.contributor.authorZhao, Aihua-
dc.contributor.authorWu, Qing-
dc.contributor.authorKuang, Junliang-
dc.contributor.authorSun, Dongnan-
dc.contributor.authorRen, Zhenxing-
dc.contributor.authorLi, Mengci-
dc.contributor.authorZhao, Mingliang-
dc.contributor.authorWang, Shouli-
dc.contributor.authorBao, Yuqian-
dc.contributor.authorLi, Huating-
dc.contributor.authorHu, Cheng-
dc.contributor.authorDong, Bing-
dc.contributor.authorLi, Defa-
dc.contributor.authorWu, Jiayu-
dc.contributor.authorXia, Jialin-
dc.contributor.authorWang, Xuemei-
dc.contributor.authorLan, Ke-
dc.contributor.authorRajani, Cynthia-
dc.contributor.authorXie, Guoxiang-
dc.contributor.authorLu, Aiping-
dc.contributor.authorJia, Weiping-
dc.contributor.authorJiang, Changtao-
dc.contributor.authorJia, Wei-
dc.date.accessioned2024-04-17T07:05:02Z-
dc.date.available2024-04-17T07:05:02Z-
dc.date.issued2021-
dc.identifier.citationCell Metabolism, 2021, v. 33, n. 4, p. 791-803.e7-
dc.identifier.issn1550-4131-
dc.identifier.urihttp://hdl.handle.net/10722/342612-
dc.description.abstractHyocholic 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.-
dc.languageeng-
dc.relation.ispartofCell Metabolism-
dc.subjectbile acid-
dc.subjectdiabetes-
dc.subjectFXR-
dc.subjectglucagon-like peptide-1-
dc.subjectglucose homeostasis-
dc.subjecthyocholic acid-
dc.subjecthyodeoxycholic acid-
dc.subjectinsulin-
dc.subjectpig-
dc.subjectTGR5-
dc.titleHyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.cmet.2020.11.017-
dc.identifier.pmid33338411-
dc.identifier.scopuseid_2-s2.0-85099251673-
dc.identifier.volume33-
dc.identifier.issue4-
dc.identifier.spage791-
dc.identifier.epage803.e7-
dc.identifier.eissn1932-7420-
dc.identifier.isiWOS:000637370500014-

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