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Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells

OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G(αq)-coupled free fatty ac...

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Autores principales: Goldspink, Deborah A., Lu, Van B., Billing, Lawrence J., Larraufie, Pierre, Tolhurst, Gwen, Gribble, Fiona M., Reimann, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784317/
https://www.ncbi.nlm.nih.gov/pubmed/29167062
http://dx.doi.org/10.1016/j.molmet.2017.11.005
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author Goldspink, Deborah A.
Lu, Van B.
Billing, Lawrence J.
Larraufie, Pierre
Tolhurst, Gwen
Gribble, Fiona M.
Reimann, Frank
author_facet Goldspink, Deborah A.
Lu, Van B.
Billing, Lawrence J.
Larraufie, Pierre
Tolhurst, Gwen
Gribble, Fiona M.
Reimann, Frank
author_sort Goldspink, Deborah A.
collection PubMed
description OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G(αq)-coupled free fatty acid receptors FFA1 and G(αs)-coupled bile acid receptors GPBAR1. METHODS: Experiments were performed using ileal organoids generated from mice transgenically expressing fluorescent reporters (Epac2-camps and GCaMP3) under control of the proglucagon promoter. Electrophysiology and single cell imaging were performed on identified L-cells in organoids, and GLP-1 secretion from cultured organoids was measured by immunoassay. RESULTS: The FFA1 ligand TAK-875 triggered L-cell electrical activity, increased intracellular calcium, and activated a depolarizing current that was blocked by the TRPC3 inhibitor Pyr3. TAK-875 triggered GLP-1 secretion was Pyr3 sensitive, suggesting that the TRPC3 channel links FFA1 activation to calcium elevation and GLP-1 release in L-cells. GPBAR1 agonist triggered PKA-dependent L-type Ca(2+) current activation and action potential firing in L-cells. The combination of TAK-875 and a GPBAR1 agonist triggered synergistic calcium elevation and GLP-1 secretory responses. CONCLUSIONS: FFA1 and GPBAR1 activation individually increased electrical activity in L-cells by recruiting pathways that include activation of TRPC3 and L-type voltage-gated Ca(2+) channels. Synergy between the pathways activated downstream of these receptors was observed both at the level of Ca(2+) elevation and GLP-1 secretion.
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spelling pubmed-57843172018-01-29 Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells Goldspink, Deborah A. Lu, Van B. Billing, Lawrence J. Larraufie, Pierre Tolhurst, Gwen Gribble, Fiona M. Reimann, Frank Mol Metab Original Article OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G(αq)-coupled free fatty acid receptors FFA1 and G(αs)-coupled bile acid receptors GPBAR1. METHODS: Experiments were performed using ileal organoids generated from mice transgenically expressing fluorescent reporters (Epac2-camps and GCaMP3) under control of the proglucagon promoter. Electrophysiology and single cell imaging were performed on identified L-cells in organoids, and GLP-1 secretion from cultured organoids was measured by immunoassay. RESULTS: The FFA1 ligand TAK-875 triggered L-cell electrical activity, increased intracellular calcium, and activated a depolarizing current that was blocked by the TRPC3 inhibitor Pyr3. TAK-875 triggered GLP-1 secretion was Pyr3 sensitive, suggesting that the TRPC3 channel links FFA1 activation to calcium elevation and GLP-1 release in L-cells. GPBAR1 agonist triggered PKA-dependent L-type Ca(2+) current activation and action potential firing in L-cells. The combination of TAK-875 and a GPBAR1 agonist triggered synergistic calcium elevation and GLP-1 secretory responses. CONCLUSIONS: FFA1 and GPBAR1 activation individually increased electrical activity in L-cells by recruiting pathways that include activation of TRPC3 and L-type voltage-gated Ca(2+) channels. Synergy between the pathways activated downstream of these receptors was observed both at the level of Ca(2+) elevation and GLP-1 secretion. Elsevier 2017-11-11 /pmc/articles/PMC5784317/ /pubmed/29167062 http://dx.doi.org/10.1016/j.molmet.2017.11.005 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Goldspink, Deborah A.
Lu, Van B.
Billing, Lawrence J.
Larraufie, Pierre
Tolhurst, Gwen
Gribble, Fiona M.
Reimann, Frank
Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title_full Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title_fullStr Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title_full_unstemmed Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title_short Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
title_sort mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784317/
https://www.ncbi.nlm.nih.gov/pubmed/29167062
http://dx.doi.org/10.1016/j.molmet.2017.11.005
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