Bile acid receptors as targets for drug development

Schaap, Frank G.; Trauner, Michael; Jansen, Peter L. M.

doi:10.1038/nrgastro.2013.151

Cited by 701Drug Transport and Resistance MechanismsCholesterol and Lipid MetabolismLiver physiology and pathology

Bile acid receptors as targets for drug development

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Schaap, Frank G., Trauner, Michael, Jansen, Peter L. M.·2014·Nature Reviews Gastroenterology & Hepatology

DOI 10.1038/nrgastro.2013.151

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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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Many hepatic effects of FXR activation are mediated by intestinal FXR receptors, which cause release of FGF19 that acts on liver targets.
“Many of the hepatic effects of FXR activation are mediated by intestinal FXR receptors, resulting in the release of FGF19, which then acts on targets in the liver136–139.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [136]
FXR is a bile acid receptor that mediates effects on the intestinal epithelial barrier and multiple liver effects including suppression of bile acid synthesis, inhibition of liver inflammation, promotion of liver regeneration and tumour suppression.
“FXR is a receptor for bile acids that mediates their effects on the intestinal epithelial barrier as well as multiple effects on the liver, such as suppression of bile acid synthesis, inhibition of liver inflammation, promotion of liver regeneration and tumour suppression (reviewed elsewhere136).”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [136]

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Identification of a hormonal basis for gallbladder filling
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Tauroursodesoxycholate-induced choleresis involves p38MAPK activation and translocation of the bile salt export pump in rats
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Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism
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Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome
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Bile acid metabolism and signaling in liver disease and therapy
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Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice
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Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal
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Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview
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INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats
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Bile acid receptors as targets for drug
Schaap, G., Trauner, M. A., & Jansen, P. L. M. (2013)
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Authors: Schaap, F. G., Trauner, M., & Jansen, P. L. M.
Affiliations: Maastricht University (NL)
Medical University of Vienna (AT)
Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author: Jansen, Peter L. M.
ORCID: Schaap, Frank G.
Trauner, Michael
Venue: Nature Reviews Gastroenterology & Hepatology
Publisher: Springer Science and Business Media LLC
Published: 2013-08-27
Volume: 11
Issue: 1
Pages: 55-67
ISSN: 1759-5045 (ISSN-L)
1759-5053
DOI: 10.1038/nrgastro.2013.151
OpenAlex: W2022279737
Cited by: 696
References: 170
Citations by year: 2026: 40 · 2025: 36 · 2024: 50 · 2023: 58 · 2022: 74 · 2021: 80 · 2020: 67 · 2019: 61 · 2018: 62 · 2017: 49 · 2016: 56 · 2015: 32 · 2014: 30 · 2013: 1
FWCI: 4.27
Type: journal article
Language: en
Open access: green
zenodo.org
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature Reviews Gastroenterology & Hepatology (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Research Publications (Maastricht University) (submittedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Funders: CYTED Ciencia y Tecnología para el Desarrollo
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: bile acid receptors, bile acid signaling, farnesoid X receptor, TGR5, G protein-coupled receptors, nuclear receptors, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, bile acid analogues, drug development, chronic liver disease, hepatocellular carcinoma, inflammation, fibrosis, metabolic disorders, cholesterol metabolism
MeSH terms: Animals, Bile Acids and Salts, Disease Models, Animal, Drug Therapy, Humans, Inflammation, Liver Diseases, Liver Neoplasms, Metabolic Diseases, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Mice

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Bile acid receptors as targets for drug development

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