Nuclear receptors as therapeutic targets in cholestatic liver diseases

Zollner, Gernot; Trauner, Michael

doi:10.1111/j.1476-5381.2008.00030.x

Cited by 146Drug Transport and Resistance MechanismsCholesterol and Lipid MetabolismLiver Diseases and Immunity

Nuclear receptors as therapeutic targets in cholestatic liver diseases

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Zollner, Gernot, Trauner, Michael·2009·British Journal of Pharmacology

DOI 10.1111/j.1476-5381.2008.00030.xPMC PMC2697779

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Abstract

Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors including the farnesoid X receptor, pregnane X receptor, vitamin D receptor and constitutive androstane receptor, which target overlapping, although not identical, sets of genes. Because the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis, therapeutic targeting of these receptors via specific and potent agonists may further enhance the hepatic defence against toxic bile acids. Activation of these receptors results in repression of bile acid synthesis, induction of phases I and II bile acid hydroxylation and conjugation and stimulation of alternative bile acid export while limiting hepatocellular bile acid import. Furthermore, the use of nuclear receptor ligands may not only influence bile acid transport and metabolism but may also directly target hepatic fibrogenesis and inflammation. Many drugs already used to treat cholestasis and its complications such as pruritus (e.g. ursodeoxycholic acid, rifampicin, fibrates) may act via activation of nuclear receptors. More specific and potent nuclear receptor ligands are currently being developed. This article will review the current knowledge on nuclear receptors and their potential role in the treatment of cholestatic liver diseases.

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Nuclear receptors are ligand-activated transcription factors that regulate gene expression of key molecular signals involved in liver fibrosis.
“Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis.”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [25]
All nuclear receptors share a common structure that allows them to bind directly to DNA and regulate gene transcription.
“All NRs share a common structure which allows them to bind directly to DNA and regulate gene transcription.[25]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [25]
Nuclear receptors play a pivotal role in the overall control of several biological processes and represent a promising target in liver diseases.
“NRs in general, play a pivotal role in the overall control of several biological processes and represent a promising target in liver diseases.[25]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [25]
In addition to FXR, other nuclear receptors such as PXR, CAR and VDR are activated by certain bile acids.
“In addition to FXR also other NRs such as the pregnane X receptor (PXR/NR1I2), the constitutive androstane receptor (CAR/NR1I3) and the vitamin D receptor (NR1I1) are activated via certain BAs.45”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [45]
Pharmacological activation of FXR restores BA homoeostasis by stimulating BSEP transcription, reducing BA uptake and synthesis, and stimulating alternative basolateral export, thereby reducing hepatic BA load and alleviating BA-mediated cellular stress in cholestasis.
“pharmacological activation of FXR restores BA homoeostasis by stimulation of transcription of the bile salt export pump that mediates the rate-limiting step in hepatocellular BA excretion across the canalicular membrane. Together with a reduction of BA uptake systems Na +- taurocholate cotransporting polypeptide (NTCP) and synthesis (CYP7A1) as well as stimulation of alternative basolateral export”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [45]

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Research works printed but not linked: 6

Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG Targeting nuclear receptors in cholestasis 22 G Zollner and M Trauner British Journal of Pharmacology (2009) 156 7-27
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Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL Targeting nuclear receptors in cholestasis 24 G Zollner and M Trauner British Journal of Pharmacology (2009) 156 7-27
Verreault M, Senekeo-Effenberger K, Trottier J, Bonzo JA, Belanger J, Targeting nuclear receptors in cholestasis 26 G Zollner and M Trauner British Journal of Pharmacology (2009) 156 7-27

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Authors: Zollner, G., & Trauner, M.
Affiliations: Medical University of Graz (AT)
Corresponding author: Trauner, Michael
ORCID: Zollner, Gernot
Trauner, Michael
Venue: British Journal of Pharmacology
Publisher: Wiley
Published: 2008-12-24
Volume: 156
Issue: 1
Pages: 7-27
ISSN: 0007-1188 (ISSN-L)
1476-5381
DOI: 10.1111/j.1476-5381.2008.00030.x
PMC: PMC2697779
OpenAlex: W2022838513
Cited by: 146
References: 304
Citations by year: 2026: 6 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 11 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 11 · 2015: 7 · 2014: 14 · 2013: 12 · 2012: 9
FWCI: 1.09
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Pharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords: nuclear receptors, cholestasis, cholestatic liver injury, farnesoid X receptor, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, bile acid metabolism, bile acid transport, bile acid detoxification, hepatoprotection, liver fibrosis, liver cirrhosis, nuclear receptor agonists, ursodeoxycholic acid, pruritus, liver inflammation
MeSH terms: Bile Acids and Salts, Cholestasis, Chronic Disease, Humans, Ligands, Liver, Liver Cirrhosis, Receptors, Cytoplasmic and Nuclear

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Nuclear receptors as therapeutic targets in cholestatic liver diseases

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