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Bile Acids and TGR5 (Gpbar1) Signaling

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Abstract

TGR5 (Gpbar1, M-BAR) is a Gs protein-coupled, cell surface receptor responsive to bile acids as well as various steroid hormones. Ligand binding to TGR5 activates adenylate cyclase, triggers an elevation of intracellular cyclic AMP (cAMP) levels and activates further downstream signaling pathways. Moreover, TGR5 can modulate signaling of Src kinases, mitogen-activated protein (MAP) kinases, and the epidermal growth factor receptor (EGFR) independent of adenylate cyclase activation.

TGR5 is expressed almost ubiquitously in human and rodent tissues, with high mRNA levels being present in the stomach as well as in the small and large intestine, the liver, the spleen, the kidney but also in the adrenal glands, the placenta, and the brain. It is likely that TGR5 functions predominately as a bile acid receptor in organs participating in bile acid synthesis, secretion and reabsorption such as liver, intestine and kidney, while TGR5 may represent a cell surface-bound steroid receptor in other organs.

In line with the broad expression, TGR5 exerts multiple functions comprising the modulation of bile acid homeostasis, bile secretion, gallbladder filling, intestinal motility, glucose homeostasis, energy expenditure, and immune functions. Furthermore, activation of TGR5 can attenuate weight gain and atherosclerosis development, improve glycemic control and reduce hepatic steatosis in mice fed a high fat diet. However, through TGR5, bile acids can induce itch and proliferation of cystic and malignant-transformed cholangiocytes. While activation of TGR5 has beneficial effects in metabolic and inflammatory disease models, inhibition of TGR5 signaling may have therapeutic potential in cholestatic pruritus, cholangiocarcinoma, and polycystic liver disease.

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Authors and Affiliations

  1. Düsseldorf, Germany

    Verena Keitel, Christoph G. W. Gertzen, Sven Schäfer, Caroline Klindt, Christina Wöhler, Kathleen Deutschmann, Maria Reich, Holger Gohlke & Dieter Häussinger

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  1. Verena Keitel
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  2. Christoph G. W. Gertzen
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Correspondence to Verena Keitel .

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  1. Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    Damjana Rozman

  2. Rudolf Schönheimer Institute of Biochemistry, Department of General Biochemistry, University of Leipzig, Faculty of Medicine, Leipzig, Germany

    Rolf Gebhardt

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Keitel, V. et al. (2020). Bile Acids and TGR5 (Gpbar1) Signaling. In: Rozman, D., Gebhardt, R. (eds) Mammalian Sterols . Springer, Cham. https://doi.org/10.1007/978-3-030-39684-8_4

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