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

Abstract

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.

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

“…FXR and TGR5 receptors are widely expressed, and may even be found on pancreatic ␤ cells (6,(13)(14)(15). In fact, systemic bile acids seem to stimulate TGR5 and FXR, which positions postprandial plasma bile acids suitable for the regulation of overall glucose homeostasis (1,6,16,17). Such a concept could fit with the established notion that, in T2D patients with a relatively low HbA1c (ϳ7.5% [58 mmol/mol] or less), postprandial glycemia, as opposed to preprandial blood glucose, makes the predominant contribution to overall glycemic control (10).…”

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

“…leading to release of L-cell gut peptides 84 . In humans, administration of BAs has been associated with increased plasma GLP-1 levels and improved glucose homeostasis.…”

Bile Acid Uptake Transporters as Targets for Therapy

“…This effect seems mostly mediated by TGR5 activation [63,64], and partially through the inhibition of FXR signaling [65]. Bile acid-induced GLP1 release occurs upon the activation of TGR5 at the basolateral (blood) side of L-cells [66,67]. Nevertheless, ASBT inhibitors and bile acid-binding resins both stimulate the release of enterohepatic hormones, including GLP-1, and inhibit the uptake of bile acid into the circulation.…”