Systemic bile acid sensing by G protein‐coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP‐1 release
Open accessAbstract
Background and Purpose: Nutrient sensing in the gut is believed to be accomplished through activation of GPCR s 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.
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Bacteria-derived secondary bile acids (lithocholic acid, deoxycholic acid) can activate the G-protein coupled bile acid receptor TGR5 in L cells, promoting peripheral release of GLP-1 and PYY.
“Bacteria-derived secondary bile acids (lithocholic acid, deoxycholic acid) can activate the G-protein coupled bile acid receptor Gpbar1 receptor (TGR5) in L cells, promoting the peripheral release of GLP-1 and PYY (Katsuma et al., 2005;Thomas et al., 2009;Ullmer et al., 2013).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Ullmer et al., 2013
The Introduction identifies GPBAR1 as TGR5 and reports that deoxycholic acid increased plasma PYY; the pharmacological characterization shows that lithocholic acid activates GPBAR1. The section on systemic RO5527239 exposure reports GLP-1 and PYY release from L-cells after activation with a synthetic agonist. These passages do not establish that both named bile acids promote peripheral release of both peptides, or state that they are bacteria-derived. (LLM, conf=0.87)
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Cites
Guide to receptors and channels (GRAC), 5th edition
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“Transcriptional analysis of primary L-cells revealed the presence of several GPCRs that are responsive to regulators such as the acylethanolamine receptor GPR119, the long-chain fatty acid receptors GPR40 and GPR120, the BA receptor GPBAR1 (Reimann et al., 2008) and the short-chain fatty acid receptor GPR41 (Samuel et…”
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Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance
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Bile acid signaling pathways from the enterohepatic circulation to the central nervous system
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- Authors
- Ullmer, C., Alvarez Sanchez, R., Sprecher, U., Raab, S., Mattei, P., Dehmlow, H., Sewing, S., Iglesias, A., Beauchamp, J., & Conde‐Knape, K.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Non‐Clinical Safety F. Hoffmann‐La Roche AG Basel Switzerland
- Corresponding author
- Ullmer, C
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2013-05-16
- Volume
- 169
- Issue
- 3
- Pages
- 671-684
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3682713
- OpenAlex
- W1564206240
- Cited by
- 92
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 3 · 2021: 15 · 2020: 15 · 2019: 12 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 1 · 2013: 2
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- TGR5, G protein-coupled bile acid receptor, peptide YY, glucagon-like peptide-1, L cells, enteroendocrine cells, gut hormone secretion, oral bioavailability, glucose tolerance, systemic exposure, nutrient sensing
- MeSH terms
- Animals, Cell Line, Cricetulus, Diabetes Mellitus, Type 2, Gastrointestinal Agents, Humans, Hypoglycemic Agents, Isonipecotic Acids, Macaca fascicularis, Male, Mice, Mutant Strains, Mice, Transgenic, Oximes, Piperidines, Recombinant Proteins, Taurine, CHO Cells, Enteroendocrine Cells, Peptide YY, Receptors, G-Protein-Coupled, Metabolic Detoxication, Phase II, Mice, Glucagon-Like Peptide 1
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