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dc.contributor.authorBrighton, Cheryl A
dc.contributor.authorRievaj, Juraj
dc.contributor.authorKuhre, Rune E
dc.contributor.authorGlass, Leslie L
dc.contributor.authorSchoonjans, Kristina
dc.contributor.authorHolst, Jens J
dc.contributor.authorGribble, Fiona M
dc.contributor.authorReimann, Frank
dc.identifier.citationEndocrinology 2015, 156(11), 3961-3970. doi: 10.1210/en.2015-1321
dc.description.abstractBile acids are well-recognized 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 and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine 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 that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than 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 nonpolarized 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 postabsorptive 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.publisherThe Endocrine Society
dc.rightsAttribution 2.0 UK: England & Wales
dc.titleBile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
dc.description.versionThis is the final version of the article. It first appeared from Endocrine Society via
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
dc.contributor.orcidGlass, Leslie [0000-0002-3559-4705]
dc.contributor.orcidGribble, Fiona [0000-0002-4232-2898]
dc.contributor.orcidReimann, Frank [0000-0001-9399-6377]
rioxxterms.typeJournal Article/Review
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-idMedical Research Council (MC_UU_12012/3)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5/B)
pubs.funder-project-idEuropean Commission (266408)

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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