Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein–Coupled Bile Acid Receptors

Endocrinology - Tập 156 Số 11 - Trang 3961-3970 - 2015
Cheryl A. Brighton1, Juraj Rievaj1, Rune E. Kuhre2, Leslie Glass1, Kristina Schoonjans3, Jens J. Holst2, Fiona M. Gribble1, Frank Reimann1
1University 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
2 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
3Institute of Bioengineering (K.S.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland

Tóm tắt

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 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 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.

Từ khóa


Tài liệu tham khảo

Baggio, 2007, Biology of incretins: GLP-1 and GIP, Gastroenterology, 132, 2131, 10.1053/j.gastro.2007.03.054

Holst, 2007, The physiology of glucagon-like peptide 1, Physiol Rev, 87, 1409, 10.1152/physrev.00034.2006

Tolhurst, 2012, Intestinal sensing of nutrients, Handb Exp Pharmacol, 209, 309, 10.1007/978-3-642-24716-3_14

Nauck, 2011, Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications, Am J Med, 124, S3, 10.1016/j.amjmed.2010.11.002

Jørgensen, 2012, Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance, Am J Physiol Endocrinol Metab, 303, E122, 10.1152/ajpendo.00073.2012

Jørgensen, 2013, Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes, Diabetes, 62, 3044, 10.2337/db13-0022

Lefebvre, 2009, Role of bile acids and bile acid receptors in metabolic regulation, Physiol Rev, 89, 147, 10.1152/physrev.00010.2008

Parker, 2012, Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion, Br J Pharmacol, 165, 414, 10.1111/j.1476-5381.2011.01561.x

Thomas, 2009, TGR5-mediated bile acid sensing controls glucose homeostasis, Cell Metab, 10, 167, 10.1016/j.cmet.2009.08.001

Patti, 2009, Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism, Obesity (Silver Spring), 17, 1671, 10.1038/oby.2009.102

Jørgensen, 2015, Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations, J Clin Endocrinol Metab, 100, E396, 10.1210/jc.2014-1658

Ullmer, 2013, Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release, Br J Pharmacol, 169, 671, 10.1111/bph.12158

Li, 2011, The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling, Mol Endocrinol, 25, 1066, 10.1210/me.2010-0460

Duan, 2015, Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes, J Med Chem, 58, 3315, 10.1021/jm500829b

Reimann, 2008, Glucose sensing in L cells: a primary cell study, Cell Metab, 8, 532, 10.1016/j.cmet.2008.11.002

Parker, 2012, Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion, Diabetologia, 55, 2445, 10.1007/s00125-012-2585-2

Luche, 2007, Faithful activation of an extra-bright red fluorescent protein in “knock-in” Cre-reporter mice ideally suited for lineage tracing studies, Eur J Immunol, 37, 43, 10.1002/eji.200636745

Zariwala, 2012, A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo, J Neurosci, 32, 3131, 10.1523/JNEUROSCI.4469-11.2012

Nikolaev, 2004, Novel single chain cAMP sensors for receptor-induced signal propagation, J Biol Chem, 279, 37215, 10.1074/jbc.C400302200

Friedlander, 2011, Role of phosphodiesterase and adenylate cyclase isozymes in murine colonic glucagon-like peptide 1 secreting cells, Br J Pharmacol, 163, 261, 10.1111/j.1476-5381.2010.01107.x

Psichas, 2015, Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells

Emery, 2015, Stimulation of GLP-1 secretion downstream of the ligand-gated ion channel TRPA1, Diabetes, 64, 1202, 10.2337/db14-0737

Kuhre, 2015, Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine, Diabetes, 64, 370, 10.2337/db14-0807

Orskov, 1991, Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine, J Clin Invest, 87, 415, 10.1172/JCI115012

Keitel, 2009, The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders, Hepatology, 50, 861, 10.1002/hep.23032

Kawamata, 2003, A G protein-coupled receptor responsive to bile acids, J Biol Chem, 278, 9435, 10.1074/jbc.M209706200

Geraedts, 2012, Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery, Am J Physiol Endocrinol Metab, 303, E464, 10.1152/ajpendo.00163.2012

Joshi, 2013, Endogenous PYY and GLP-1 mediate l-glutamine responses in intestinal mucosa, Br J Pharmacol, 170, 1092, 10.1111/bph.12352

Patel, 2014, Gastrointestinal hormonal responses on GPR119 activation in lean and diseased rodent models of type 2 diabetes, Int J Obes (Lond), 38, 1365, 10.1038/ijo.2014.10

Zhou, 2014, Structural basis of the alternating-access mechanism in a bile acid transporter, Nature, 505, 569, 10.1038/nature12811

Gribble, 2003, A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line, Diabetes, 52, 1147, 10.2337/diabetes.52.5.1147

Sun, 2006, Identification of functionally relevant residues of the rat ileal apical sodium-dependent bile acid cotransporter, J Biol Chem, 281, 16410, 10.1074/jbc.M600034200

Voronina, 2002, Bile acids induce calcium signals in mouse pancreatic acinar cells: implications for bile-induced pancreatic pathology, J Physiol, 540, 49, 10.1113/jphysiol.2002.017525

Habib, 2012, Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry, Endocrinology, 153, 3054, 10.1210/en.2011-2170

Lefèvre, 2014, Pharmacological and electrophysiological characterization of the human bile acid-sensitive ion channel (hBASIC), Pflugers Arch, 466, 253, 10.1007/s00424-013-1310-4

Garg, 2011, Effects of colesevelam on LDL-C, A1c and GLP-1 levels in patients with type 1 diabetes: a pilot randomized double-blind trial, Diabetes Obes Metab, 13, 137, 10.1111/j.1463-1326.2010.01320.x

Chen, 2010, Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats, J Pharmacol Exp Ther, 334, 164, 10.1124/jpet.110.166892

Mekhjian, 1979, Colonic absorption of unconjugated bile acids: perfusion studies in man, Dig Dis Sci, 24, 545, 10.1007/BF01489324

Thông tin
Thông tin xuất bản

Endocrinology

Tập 156 Số 11

3961-3970

Thông tin tác giả