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TGR5: Pathogenetic Role and/or Therapeutic Target in Fibrosing Cholangitis?

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Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the intrahepatic and extrahepatic biliary tree leading to bile duct strictures, progressive cholestasis, and development of liver fibrosis and cirrhosis. The pathogenesis of PSC is still elusive; however, both an immune-mediated injury of the bile ducts as well as increased recruitment of intestinal-primed T lymphocytes to the biliary tracts seem to contribute to disease development and progression. TGR5 (Gpbar-1) is a G-protein-coupled receptor responsive to bile acids, which is expressed in cholangiocytes, intestinal epithelial cells, and macrophages of the liver and intestine as well as in CD14-positive monocytes of the peripheral blood. Activation of TGR5 in biliary epithelial cells promotes chloride and bicarbonate secretion, triggers cell proliferation, and prevents apoptotic cell death. In immune cells, stimulation of TGR5 inhibits cytokine expression and secretion, thus reducing systemic as well as hepatic and intestinal inflammation. The expression pattern of TGR5 in the liver and intestine as well as the potential protective functions of TGR5 suggest a role for this receptor in the pathogenesis of PSC. While mutations in the coding region of the TGR5 gene are too rare to contribute to overall disease susceptibility, the expression and localization of the receptor have not been studied in PSC livers. Pharmacological activation of TGR5 in mice promotes protective mechanisms in biliary epithelial cells and reduces hepatic and systemic inflammation; however, it also provokes pruritus. Further studies are needed to predict the potential benefits as well as side effects of TGR5 agonist treatment in PSC patients.

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Abbreviations

AE:

Anionic exchanger

BEC:

Biliary epithelial cell (cholangiocyte)

CA:

Cholic acid

cAMP:

Cyclic AMP

CCA:

Cholangiocarcinoma

CDCA:

Chenodeoxycholic acid

CFTR:

Cystic fibrosis transmembrane conductance regulator

CRC:

Colorectal cancer

DCA:

Deoxycholic acid

IBD:

Inflammatory bowel disease

IL:

Interleukin

INT-777:

6α-Ethyl-23(S)-methyl-cholic acid (EMCA)

LCA:

Lithocholic acid

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor κB

PSC:

Primary sclerosing cholangitis

SNP:

Single nucleotide polymorphism

TNF-α:

Tumor necrosis factor alpha

TLCA:

Taurolithocholic acid

UC:

Ulcerative colitis

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Acknowledgments

Our research is supported by the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 974 Düsseldorf and Klinische Forschergruppe 217. We thank Mark Pruzanski, Luciano Adorini, and David Shapiro from Intercept Pharmaceuticals for providing the INT-777.

Conflict of Interest

VK, MR, and DH have no conflict of interest to declare.

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  1. Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Verena Keitel, Maria Reich & Dieter Häussinger

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  1. Verena Keitel
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Correspondence to Verena Keitel or Dieter Häussinger.

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Keitel, V., Reich, M. & Häussinger, D. TGR5: Pathogenetic Role and/or Therapeutic Target in Fibrosing Cholangitis?. Clinic Rev Allerg Immunol 48, 218–225 (2015). https://doi.org/10.1007/s12016-014-8443-x

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