A G Protein-coupled Receptor Responsive to Bile Acids*

By Y. Kawamata, Ryo Fujii, M. Hosoya, M. Harada, Hiromi Yoshida, M. Miwa, S. Fukusumi, Y. Habata, T. Itoh, Y. Shintani and 3 more. Journal of Biological Chemistry, 2003

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So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5′-O-3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.

Subfields: Molecular Biology, Oncology, Surgery

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Citations in the corpus

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, neutral): “FXR, PXR and VDR as well as the TGR5 are expressed in peripheral blood mononuclear cells, macrophages and Kupffer cells (Fiorucci et al. 2010; Graf and Bode 2012; Kawamata et al. 2003; Keitel et al. 2008b; Schote et al. 2007).”
Bile acids: regulation of synthesis (2009, background): “adipose tissue, bile acids activate TGR5, a GPCR (35, 36).”
The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity1 (2009, background): “Because these counterregulatory effects are lost in FXR / macrophages, they selectively depend on FXR expression and are not mediated by other receptors, such as the recently discovered G protein-coupled receptor TGR5, a seven-trans-membrane domain receptor for bile acids that is also expressed in m”
Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. (2016, background): “TGR5 is activated by multiple BAs, LCA being the most potent natural agonist with an EC50 of 530 nM (Kawamata et al., 2003).”
TGR5-mediated bile acid sensing controls glucose homeostasis. (2009, background): “Beyond the orchestration of BA, lipid and glucose metabolism by the nuclear receptor farnesoid X receptor (FXR), BAs also act as signaling molecules through the BA-dedicated G-protein coupled receptor (GPCR) TGR5 (GPR131) (Kawamata et al., 2003; Maruyama et al., 2002).”
Bile Acid Signaling in Metabolic Disease and Drug Therapy (2014, background): “Thus far, TGR5 activation has shown protective effects in various inflammation-related diseases in experimental models (Kawamata et al., 2003; Keitel et al., 2008).”
Pleiotropic Roles of Bile Acids in Metabolism (2013, background): “Interest in bile acids as hormones was further stimulated a decade ago when two groups independently identified a plasma membrane-bound G protein-coupled receptor that was activated by low levels (1–10 mM) of bile acids (Kawamata et al., 2003; Maruyama et al., 2002).”
Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 (2003, methodology): “MAP kinase MAP kinase activation in CHO and MIN6 cells after treatment with 10 µM of each FFA was determined as described previousl”
Systemic gut microbial modulation of bile acid metabolism in host tissue compartments (2010, background): “Although the biological significance of bile acids in the heart remains to be elucidated, given their known function as signaling molecules and the presence of the FXR and TGR5 receptors in addition to bile acid transporters in the heart (26, 27, 31, 32), it is feasible that bile acids serve a regul”
Consequences of bile salt biotransformations by intestinal bacteria (2016, background): “Starting in 1999, it became clear that bile acids also serve endocrine functions in the body largely through their binding and activation of the nuclear receptor, Farnesoid X Receptor (FXR),3,4 and the plasma membranebile acid receptor TGR5.”
Targeting bile-acid signalling for metabolic diseases (2008, background): “These arise from the fact that bile acids are ligands for both GPCRs, such as TGR5 or 'membrane bile-acid receptor”