Associate editor: P. Holzer
Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity

https://doi.org/10.1016/j.pharmthera.2010.03.005Get rights and content

Abstract

Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics such as bile acids and drugs. Research in the last two decades provided researchers and clinicians with a detailed understanding of the regulation of these processes and, most importantly, also prompted the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases. Some nuclear receptor agonists are already used in daily clinical practice but many more are currently designed or tested for the treatment of diabetes, dyslipidemia, fatty liver disease, cancer, drug hepatotoxicity and cholestasis. The hydrophilic bile acid ursodeoxycholic acid is currently the only available drug to treat cholestasis but its efficacy is limited. Therefore, development of novel treatments represents a major goal for both pharmaceutical industry and academic researchers. Targeting nuclear receptors in cholestasis is an intriguing approach since these receptors are critically involved in regulation of bile acid homeostasis. This review will discuss the general role of nuclear receptors in regulation of transporters and other enzymes maintaining bile acid homeostasis and will review the role of individual receptors as therapeutic targets. In addition, the central role of nuclear receptors and other transcription factors such as the aryl hydrocarbon receptor (AhR) and the nuclear factor-E2-related factor (Nrf2) in mediating drug disposition and their potential therapeutic role in drug-induced liver disease will be covered.

Introduction

Nuclear receptors (NRs) function as ligand-activated transcription factors that regulate the expression of target genes involved in various processes including reproduction, development, and metabolism of xeno- and endobiotics such as bile acids and drugs. NRs are critically involved in the maintenance of bile acid homeostasis and drug disposition by orchestrating the regulation of genes involved in hepatic uptake, phase I and phase II metabolism and excretion. The activity of NRs is controlled by the intracellular concentration of their specific ligands. These ligands bind to their specific NRs, activating the receptor which in turn binds to specific elements in a gene promoter resulting in stimulation or inhibition of gene expression (Karpen, 2002).

Ligand binding to NRs triggers changes in their conformation and regulates the recruitment of coregulators and chromatin-modifying machineries (Mangelsdorf & Evans, 1995). The conformational change of NRs upon ligand binding allows the dissociation of corepressors and facilitates recruitment of coactivator proteins enabling transcriptional activation (Lonard & O'Malley, 2006). All NRs share several structural domains that are essential for receptor function (Kumar et al., 2004). The carboxy-terminal region includes the ligand-binding domain, dimerization interface and a ligand-dependent activation function (Chawla et al., 2001). The NR ligand-binding domain is connected to the DNA-binding domain by a short flexible linker and mediates ligand-dependent trans-activation functions (Glass & Rosenfeld, 2000). The DNA-binding domain is highly conserved among species, is composed of two zinc fingers, and plays an important role in receptor dimerization and its binding to specific DNA sequences (Staudinger, 2008). The N-terminal region is highly variable but always contains a region called activation function 1, which is a region of the receptor involved in protein-protein interaction and transcriptional activation of target gene expression (Staudinger, 2008). Most NRs bind to their DNA response elements in a sequence-specific manner as dimers, functioning either as homodimers or as heterodimers with the retinoid X receptor (RXR) (Mangelsdorf & Evans, 1995). In the absence of a ligand, the ligand-binding domain of many NRs is bound to transcriptional corepressor complexes containing nuclear receptor corepressor (NCoR) or silencing mediator of retinoid and thyroid receptors (SMRT). These corepressors recruit transcriptional complexes that contain specific histone deacetylases silencing genes by chromatin condensation (Nishihara et al., 2004). In the presence of NR ligands, a conformational change results in the dissociation of the corepressor complex and the recruitment of coactivators such as the steroid receptor coactivator-1 promoting NR-transcriptional activation. Increasing knowledge on the three-dimensional structure of NRs (e.g. through crystallization studies) has facilitated the design of small molecules specifically targeting their ligand-binding domain (Pellicciari et al., 2005, Westin et al., 2005).

Many hepatic effects of drugs, metabolites and herbal or synthetic compounds can be explained by their actions as ligands for NRs in the liver. Classical drug receptors include the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) which are activated by xenobiotics such as rifampicin, phenobarbital, dexamethasone or statins (Urquhart et al., 2007). PXR is also activated by hydrophobic bile acids and bilirubin is a CAR ligand, suggesting an overlapping regulation of drug and bile acid metabolism. The farnesoid X receptor (FXR) is the major (‘classic’) bile acid receptor which is activated by a variety of primary and secondary bile acids. The vitamin D receptor (VDR) is activated by (the very hydrophobic bile acid) lithocholic acid (LCA) in addition to its natural ligand 1α,25-dihydroxyvitamin D3, complementing the bile acid sensing properties of FXR and PXR. Currently available therapies for liver diseases and their complications frequently target NRs. Moreover, several NRs can now be targeted by specifically designed ligands. This review will focus on the potential role of NRs as therapeutic targets in cholestatic diseases and will also cover their potential use in drug-induced hepatotoxicty.

Section snippets

Bile formation and cholestasis

The principles of bile formation will only be partially covered by this article, since detailed reviews on hepatobiliary transport systems have been provided elsewhere (Trauner and Boyer, 2003, Kullak-Ublick et al., 2004). A broad range of uptake and export systems for various biliary compounds is localized to the basolateral (sinusoidal) and canalicular (apical) membrane of the hepatocyte (Fig. 1). Bile is primarily formed by canalicular excretion of bile acids and non-bile acid organic anions

Hepatic bile acid uptake

Bile acids are able to induce a negative feedback regulating their hepatic uptake in order to maintain bile acid concentrations at constant, non-toxic levels within hepatocytes. The key NRs regulating basolateral bile uptake into the hepatocyte are FXR, the FXR target gene short heterodimer partner (SHP) and hepatocyte nuclear factor 4 alpha (HNF4α). FXR negatively regulates the main bile acid uptake system, the Na+/taurocholate cotransporter (Ntcp) via induction of SHP which in turn interferes

Nuclear receptors as therapeutic targets

Currently, ursodeoxycholic acid (UDCA) is the only FDA-approved drug for the treatment of cholestasis and its efficacy is limited to early stages of primary biliary cirrhosis (Trauner and Graziadei, 1999, Paumgartner and Pusl, 2008). Therefore, new treatments are urgently needed to treat patients with cholestatic diseases. NRs may offer novel drug targets for treatment of cholestatic liver diseases. While several, already clinically used drugs turned out to be NR ligands, more specific and

Drug detoxification and hepatotoxicity

Bile acid and bilirubin detoxification is tightly coupled to detoxification of other endo- and xenobiotics including hormones, dietary phytochemicals and drugs. Phase I, phase II and uptake and export systems are involved in metabolism of bile acids and other endo-/xenobiotics. Moreover, regulation of these enzymes is orchestrated also by overlapping or even identical sets of NRs. PXR and CAR are the key regulators of drug disposition and play an additional role in bile acid metabolism as

Conclusions

Research over the past decade since the discovery of NRs as key regulators of bile acid metabolism has allowed us not only to understand the molecular basis of bile acid homeostasis but also prompted the development of novel therapeutic approaches for cholestatic liver disease. FXR, a major bile acid receptor, has become the focus of many experimental studies which led to the development of specific ligands currently tested in the clinical setting for the treatment of cholestasis.

Acknowledgments

This work was supported by grant nos. P18613-BO5, P19118-B05, and SFB 3008 from the Austrian Science Foundation and by a GEN-AU grant from the Austrian Ministry for Science (to M.T).

References (292)

  • T. Adachi et al.

    Transport–metabolism interplay: LXR-mediated induction of human ABC transporter ABCC2 (cMOAT/MRP2) in HepG2 cells

    Mol Pharm

    (2009)
  • B. Alme et al.

    Analysis of bile acid glucuronides in urine. Identification of 3 alpha, 6 alpha, 12 alpha-trihydroxy-5 beta-cholanoic acid

    J Steroid Biochem

    (1980)
  • B. Alme et al.

    Analysis of metabolic profiles of bile acids in urine using a lipophilic anion exchanger and computerized gas–liquid chromatography-mass spectrometry

    J Lipid Res

    (1977)
  • D. Alvaro et al.

    Corticosteroids modulate the secretory processes of the rat intrahepatic biliary epithelium

    Gastroenterology

    (2002)
  • M. Ananthanarayanan et al.

    Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor

    J Biol Chem

    (2001)
  • Z. Araya et al.

    6alpha-hydroxylation of taurochenodeoxycholic acid and lithocholic acid by CYP3A4 in human liver microsomes

    Biochim Biophys Acta

    (1999)
  • F. Arenas et al.

    Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

    J Clin Invest

    (2008)
  • M. Assem et al.

    Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice

    J Biol Chem

    (2004)
  • A. Axon et al.

    A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: inhibition of NF-kappaB?

    Toxicology

    (2008)
  • T. Baba et al.

    Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction

    Mol Cell Biol

    (2005)
  • L. Bachs et al.

    Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis

    Lancet

    (1989)
  • L. Bachs et al.

    Effects of long-term rifampicin administration in primary biliary cirrhosis

    Gastroenterology

    (1992)
  • O. Barbier et al.

    Peroxisome proliferator-activated receptor alpha induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme

    J Biol Chem

    (2003)
  • O. Barbier et al.

    Lipid-activated transcription factors control bile acid glucuronidation

    Mol Cell Biochem

    (2009)
  • O. Barbier et al.

    FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity

    Gastroenterology

    (2003)
  • A.P. Beigneux et al.

    Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response

    BiochemBiophysResCommun

    (2002)
  • G.P. Berge Henegouwen et al.

    Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis

    Gut

    (1976)
  • G. Bertilsson et al.

    Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction

    Proc Natl Acad Sci USA

    (1998)
  • J.R. Bloomer et al.

    Phenobarbital effects in cholestatic liver diseases

    Ann Intern Med

    (1975)
  • K. Bodin et al.

    Novel pathways of bile acid metabolism involving CYP3A4

    Biochim Biophys Acta

    (2005)
  • A. Bremmelgaard et al.

    Bile acid profiles in urine of patients with liver diseases

    Eur J Clin Invest

    (1979)
  • A. Bremmelgaard et al.

    Hydroxylation of cholic, chenodeoxycholic, and deoxycholic acids in patients with intrahepatic cholestasis

    J Lipid Res

    (1980)
  • J.D. Brown et al.

    Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets

    Circulation

    (2007)
  • M.J. Campbell et al.

    The vitamin D receptor as a therapeutic target

    Expert Opin Ther Targets

    (2006)
  • E.L. Cancado et al.

    Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase

    Am J Gastroenterol

    (1998)
  • M. Carrella et al.

    Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an increased biosynthesis in the pravastatin-treated rat

    Hepatology

    (1999)
  • G. Castano et al.

    Influence of common gene variants of the xenobiotic receptor (PXR) in genetic susceptibility to intrahepatic cholestasis of pregnancy

    Aliment Pharmacol Ther

    (2010)
  • A. Castrillo et al.

    Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation

    Annu Rev Cell Dev Biol

    (2004)
  • B. Chatterjee et al.

    Vitamin D receptor regulation of the steroid/bile acid sulfotransferase SULT2A1

    Methods Enzymol

    (2005)
  • B. Chatterjee et al.

    Androgen and estrogen sulfotransferases of the rat liver: physiological function, molecular cloning, and in vitro expression

    Chem Biol Interact

    (1994)
  • A. Chawla et al.

    Nuclear receptors and lipid physiology: opening the X-files

    Science

    (2001)
  • C. Chen et al.

    Peroxisome proliferator-activated receptor alpha-null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure

    Toxicol Sci

    (2000)
  • C. Chen et al.

    Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile

    Drug Metab Dispos

    (2003)
  • X. Chen et al.

    Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1alpha, 25-dihydroxyvitamin D3 via the vitamin D receptor

    Mol Pharmacol

    (2006)
  • J. Cheng et al.

    Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity

    Drug Metab Dispos

    (2009)
  • J. Chianale et al.

    Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

    Biochem J

    (1996)
  • J.Y. Chiang

    Bile acids: regulation of synthesis

    J Lipid Res

    (2009)
  • J.Y. Chiang et al.

    Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha)

    Gene

    (2001)
  • I. Chisaki et al.

    Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver

    Biochim Biophys Acta

    (2009)
  • M. Choi et al.

    Therapeutic applications for novel non-hypercalcemic vitamin D receptor ligands

    Expert Opin Ther Pat

    (2009)
  • D.M. Christie et al.

    Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum

    Am J Physiol

    (1996)
  • M. Congiu et al.

    Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease

    J Gastroenterol Hepatol

    (2009)
  • A. Courtois et al.

    Up-regulation of multidrug resistance-associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone

    FEBS Lett

    (1999)
  • A.L. Craddock et al.

    Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter

    Am J Physiol

    (1998)
  • E. D'Aldebert et al.

    Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium

    Gastroenterology

    (2009)
  • J.M. de Vree et al.

    Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis

    Proc Natl Acad Sci USA

    (1998)
  • L.A. Denson et al.

    The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp

    Gastroenterology

    (2001)
  • L. Drocourt et al.

    Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes

    J Biol Chem

    (2002)
  • L. Dubuquoy et al.

    Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases

    Lancet

    (2002)
  • EASL Clinical Practice Guidelines

    Management of cholestatic liver diseases

    J Hepatol

    (2009)
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