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Signaling Pathways in Liver Diseases: PXR and CAR

  • Catherine A. M. Stedman
  • Michael Downes
  • Christopher LiddleEmail author
Chapter

Abstract

Nuclear hormone receptors (NHRs), of which there are 48 unique members in humans and 49 members in mouse, function as ligand-activated transcription factors and have critical roles in diverse cellular processes ranging from mammalian development and differentiation to metabolic homeostasis [1]. NHRs bind to the sequence-specific DNA response elements on target gene promoters as homodimers, heterodimers, or monomers. Structural and functional analyses of the NHR family have demonstrated that these receptors are comprised of functional modular domains. The DNA binding domain (DBD) consists of a well-characterized zinc finger motif that recognizes a degenerate six to eight nucleotide sequence on the target DNA. The ligand-binding domain (LBD) resides in the C-terminal portion of the protein and shares a common, predominantly alpha helical fold [1]. As implied, this domain of the receptor is where cognate ligands of the receptors interact and induce conformational changes associated with transcriptional activation. Many of the known ligands for these receptors are essential metabolic products including retinoids, thyroid hormone, vitamin D3, bile acids, oxysterols, and prostenoids that act through their cognate receptors to control metabolic homeostasis [2, 3]. The transcriptional activity of NHRs is regulated by associated factors, specifically, co-activators and co-repressors that serve as scaffolding proteins to recruit chromatin remodeling complexes which repress transcription through limiting access to gene targets, or activate transcription via unwinding chromatin. The association of co-regulators is determined by the liganded state of the receptor, as a ligand-induced conformational change promotes interaction of NHR co-­activators such as the p160 gene family [4] and P300, which recruit enzymes such as histone acetylases. Conversely, in the unliganded state the receptor is bound to scaffold co-repressors such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor co-repressor (NCoR) which recruit histone deacetylases [5].

Keywords

Bile Acid Bile Duct Ligation Constitutive Androstane Receptor Lithocholic Acid CYP3A4 Proximal Promoter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Catherine A. M. Stedman
    • 1
  • Michael Downes
    • 1
  • Christopher Liddle
    • 1
    Email author
  1. 1.Department of Clinical Pharmacology, Storr Liver UnitWestmead Millennium Institute and University of Sydney, Westmead HospitalWestmeadAustralia

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