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Bile acid receptors as targets for drug development

Key Points

  • The discovery of dedicated bile acid receptors and further research defined multiple bile acid signalling routes affecting bile acid synthesis, lipid synthesis, gluconeogenesis, inflammation, liver fibrosis and cancer

  • Steroidal and nonsteroidal agonists of bile acid receptors have been developed as potential treatments for cholestatic and metabolic liver diseases, including primary biliary cirrhosis, primary sclerosing cholangitis and NASH

  • Randomized, placebo-controlled clinical trials for the treatment of primary biliary cirrhosis and NASH with the farnesoid X receptor (FXR) agonist obeticholic acid are the first clinical trials initiated

  • Future indications for FXR and TGR5 agonists include genetic cholestatic syndromes, intrahepatic cholestasis of pregnancy, atherosclerosis, IBS, bile-reflux oesophagitis, IBD, hepatocellular and colon carcinoma

Abstract

The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.

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Figure 1: Enterohepatic actions of FXR.
Figure 2: TGR5-expressing tissues and targets.
Figure 3: Steroidal and nonsteroidal agonists of FXR and TGR5.
Figure 4: Potential targets of FXR and TGR5 agonists in NASH.
Figure 5: Bile acid receptor activation after Roux-en-Y gastric bypass surgery.

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Acknowledgements

The authors of this Review are supported by grantsP19118-B05, F3008 and F3517-B20 from the Austrian Science Foundation and European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement HEALTH-F2-2009-241762 for the project FLIP (M. Trauner) and the Dutch Digestive Diseases Foundation (MLDS WO 08-69; to P. L. M. Jansen and F. G. Schaap).

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P. L. M. Jansen and F. G. Schaap wrote the article. M. Trauner reviewed and edited the manuscript before submission.

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Correspondence to Peter L. M. Jansen.

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M. Trauner has received unrestricted research grants from Falk Pharma and Intercept and acts as an advisor for Phenex. The Medical University of Graz has filed a patent on the medical use of norUDCA and M. Trauner is listed as co-inventor. F. G. Schaap and P. L. M. Jensen declare no competing interests.

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Schaap, F., Trauner, M. & Jansen, P. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 11, 55–67 (2014). https://doi.org/10.1038/nrgastro.2013.151

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