Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
Bile 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.
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Cheryl A
CA
Brighton
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Juraj
J
Rievaj
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Rune E
RE
Kuhre
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Leslie L
LL
Glass
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Kristina
K
Schoonjans
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Jens J
JJ
Holst
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Fiona M
FM
Gribble
University of Cambridge (C.A.B., J.R., L.L.G., F.M.G., F.R.), Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (R.E.K., J.J.H.), the Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
Frank
F
Reimann
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013657:Taurodeoxycholic Acid / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000494:pharmacology; D046509:Tissue Culture Techniques
D001647:Bile Acids and Salts; C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013657:Taurodeoxycholic Acid; D013658:Taurolithocholic Acid; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D002118:Calcium