Systemic bile acid sensing by G protein‐coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP‐1 release

Abstract

Background and Purpose Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L‐cells located predominantly in distal regions of the gut secrete glucagon‐like peptide 1 (GLP‐1) and peptide tyrosine‐tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L‐cells stimulated by the BA receptor G protein‐coupled bile acid receptor 1 (GPBAR1). Experimental Approach A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L‐cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro‐RO5527239, the acute secretion effects on L‐cells were addressed via different routes of administration. Key Results GPBAR1 signalling triggers the co‐secretion of PYY and GLP‐1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro‐RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. Conclusion and Implications Selective GPBAR1 activation elicits a strong secretagogue effect on L‐cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal‐distal loop that mediates the early phase of nutrient‐evoked L‐cell secretion effects.

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).…”

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.…”

Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

“…These included some G-protein coupled receptors (GPCRs) that are known to be involved in chemical sensing in the intestinal tract, such as Gpbar1 [13] and Ffar2 [14] , as well as a large number of G-protein receptors of the olfactory receptor family and several of the vomeronasal receptor family. As discussed below, this suggests that the loss of NKCC1 affects chemosensing in the intestinal tract, and also suggests that olfactory and vomeronasal receptors play a major role in this process.…”

“…In fact, some of the GPCRs identified as differentially expressed in our microarray analyses have been shown to play important roles in chemosensing in the gut. Gpbar1 (1.47-fold increase) is expressed in enteroendocrine L-cells, where it senses bile acids and transduces a signal that leads to secretion of glucagonlike peptide 1 (GLP-1) and peptide tyrosine-tyrosine, thereby regulating glucose homeostasis [13,24] . Ffar2 (-1.85-fold decrease) is expressed in enteroendocrine cells and serves as a sensor of short-chain fatty acids [14] .…”