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dc.contributor.authorBrighton, Cheryl Aen
dc.contributor.authorRievaj, Jurajen
dc.contributor.authorKuhre, Rune Een
dc.contributor.authorGlass, Leslieen
dc.contributor.authorSchoonjans, Kristinaen
dc.contributor.authorHolst, Jens Jen
dc.contributor.authorGribble, Fionaen
dc.contributor.authorReimann, Franken
dc.date.accessioned2015-08-20T11:16:12Z
dc.date.available2015-08-20T11:16:12Z
dc.date.issued2015-08-17en
dc.identifier.citationEndocrinology 2015, 156(11), 3961-3970. doi: 10.1210/en.2015-1321en
dc.identifier.issn0013-7227
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/250333
dc.description.abstractBile acids are well recognised stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G-protein coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor FXR and apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release, and whether bile acids target their receptors on GLP-1 secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells we observed taurodeoxycholate (TDCA) and taurolithocholate (TLCA) to increase intracellular cAMP and Ca2+. In primary intestinal cultures TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca2+-response to TDCA. Using small volume Ussing chambers optimised for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral then from the luminal direction, and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in non-polarised primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include post-absorptive mechanisms.
dc.description.sponsorshipMesoscale GLP-1 immuno assays were performed by Keith Burling and colleagues at the Medical Research Council Metabolic Diseases Unit, Cambridge. Thisworkwas supported by the Wellcome Trust (grants 084 210/Z/07/Z, 088 357/Z/09/Z and 099 825/Z/12/Z) and the MRC (grant MRC_MC_UU_12012/ 3), the Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark) and the European Union’s Seventh Framework Programme for Research, Technological Development, and Demonstration Activities (Grant No. 266 408) Juraj Rievaj was supported by an EFSD Albert Renold Travel Fellowship. Ussing chamber equipment was initially kindly lent by Dr. Todd Alexander, Departments of Pediatrics& Physiology, University of Alberta, Canada.
dc.languageEnglishen
dc.language.isoenen
dc.publisherEndocrine Society
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleBile acids trigger GLP-1 release predominantly by accessing basolaterally-located G-protein coupled bile acid receptorsen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Endocrine Society via http://dx.doi.org/10.1210/en.2015-1321en
prism.endingPage3970
prism.publicationDate2015en
prism.publicationNameEndocrinologyen
prism.startingPage3961
prism.volume156en
dc.rioxxterms.funderMRC
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderNovo Nordisk Foundation
dc.rioxxterms.funderEuropean Union’s Seventh Framework Programme
dc.rioxxterms.funderEFSD Albert Renold Travel Fellowship
dc.rioxxterms.projectid084 210/Z/07/Z
dc.rioxxterms.projectid088 357/Z/09/Z
dc.rioxxterms.projectid099 825/Z/12/Z
dc.rioxxterms.projectidMRC_MC_UU_12012/ 3
dc.rioxxterms.projectid266 408
rioxxterms.versionofrecord10.1210/en.2015-1321en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-08-17en
dc.contributor.orcidGlass, Leslie [0000-0002-3559-4705]
dc.contributor.orcidGribble, Fiona [0000-0002-4232-2898]
dc.contributor.orcidReimann, Frank [0000-0001-9399-6377]
dc.identifier.eissn1945-7170
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (088357/Z/09/Z)
pubs.funder-project-idWellcome Trust (084210/Z/07/Z)
pubs.funder-project-idWellcome Trust (099825/Z/12/Z)
pubs.funder-project-idMRC (MC_UU_12012/3)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5/B)
pubs.funder-project-idMRC (MC_UU_12012/5)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales