Associate editor: P. HolzerNuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity☆
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).
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Please note that human genes and their products are capitalized, whereas rodent genes and their products are written in lower case. Transporter genes are set in italics whereas gene products are set in normal font.