期刊
MOLECULAR METABOLISM
卷 11, 期 -, 页码 84-95出版社
ELSEVIER
DOI: 10.1016/j.molmet.2018.03.007
关键词
Bile-acids; GLP-1; Neurotensin; Insulin; PYY; TGR5
资金
- Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark)
- Novo Nordisk Foundation [NNF15OC0016574]
- European Research Council [695069]
- European Union [266408]
- Medical Research Council [MRC_MC_UU_12012/3]
- [WT106262/Z/14/Z]
- [WT106263/Z/14/Z]
- MRC [MC_UU_12012/3, MC_UU_00014/3, MC_UU_00014/5] Funding Source: UKRI
Objective: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. Methods: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. Results: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP), and glucagon like peptide-1 (GLP-1), but also glucagon and insulin in vivo, to levels comparable to those resulting from glucose stimulation. The mechanisms of GLP-1, neurotensin, and peptide YY (PYY) secretion was secondary to intestinal absorption and depended on activation of basolateral membrane Takeda G-protein receptor 5 (TGR5) receptors on the L-cells in the following order of potency: Lithocholic acid (LCA) >Deoxycholicacid (DCA)> Chenodeoxycholicacid (CDCA)> Cholic acid (CA). Thus BAs did not stimulate secretion of GLP-1 and PYY from perfused small intestine in TGR5 KO mice but stimulated robust responses in wild type littermates. TGR5 is not expressed on alpha-cells or beta-cells, and BAs had no direct effects on glucagon or insulin secretion from the perfused pancreas. Conclusion: BAs should be considered not only as fat emulsifiers but also as important regulators of appetite-and metabolism-regulating hormones by activation of basolateral intestinal TGR5. (C) 2018 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license.
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