# The Nuclear Receptor PXR in Chronic Liver Disease
## 2 PXR Structure, Expression, and Activation
Two mechanisms have been proposed for PXR activation, i.e., the indirect and the direct mechanisms [4]. Although the \"ligand-binding model\" (direct) is the most popular, a non-classical (indirect) model of PXR activation has been recently investigated. This is based on the fact that several signaling pathways might alter the phosphorylation of PXR and/or associated proteins, leading to modifications of its activation [4]. For instance, in vivo studies assessed that forskolin triggers protein kinase A (PKA) signaling, enhancing the PXR-mediated induction of CYP3A4 in hepatocytes, upon recruitment of peroxisome proliferatorator-activated receptor gamma (PPAR\(\gamma\)) coactivator-1 [4; 19]. PKA signaling is also responsible for the binding between the coactivator SRC-1 and PXR. On the other hand, protein kinase C (PKC) signaling recruits corepressors, such as the nuclear receptor corepressor 1 (Ncor1), thereby inhibiting PXR activity [22]. By contrast, the direct mechanism of action is well-known and widespread among NRs and consists in the translocation of cytoplasmic PXR to the nucleus induced by ligand binding [23]. Upon ligand binding, the transactivation domains AF-1 and AF-2 act as interfaces of PXR since they mediate the recruitment of coreglators on specific target genes [5]. Interestingly, AF-2 plays a key role in defining the fate of PXR ligands as agonists or antagonists. When the AF-2 helix is placed in an \"inward\" spot, a compound is defined as an agonist, while an \"outward\" status of the helix imparts to the ligand an antagonist function [18]. Once in the nucleus, the ligand-PXR complex first binds to the retinoid X receptor \(\alpha\) (RXR\(\alpha\)), forming an heterotetrametric complex with the coactivator SRC-1 (Figure 1b), thereby enhancing the binding of the highly conserved zinc-fingers motifs present in the DBD to multiple DNA response elements in the promoter region of target genes [4; 18; 19]. Coactivators further recruit secondary coactivators and chromatin-associated enzyme, such as histone acetyltransferase (HAT), forming a multiprotein coactivator complex [24]. This prototypical transcriptional complex reorganizes the chromatin of the target genes, allowing the entrance of the transcriptional components of RNA polymerase II [7; 23]. Conversely,  
Figure 1: PXR structure (**a**) and activation following ligand binding (**b**). Upon ligand binding, PXR enters the nucleus and forms a complex with RXR. The recruitment of the coactivators HAT and SRC-1 into the complex further promotes PXR binding to DNA response elements, allowing the entrance of RNA polymerase II that starts gene transcription. HDAC downregulates PXR transcriptional activity. Abbreviations: DNA-binding domain (DBD), ligand-binding region (LBD), steroid receptor coactivator-1 (SRC-1), retinoid X receptor (RXR), histone acetyltransferase (HAT), histone deacetylase (HDAC). the recruitment of histone deacetylases (HDACs) by corepressors downregulates gene transcription [7]. Upon binding to DNA response elements, PXR transcriptional activity regulates the expression of DMETs, e.g., CYP3A4, CYP2B, glutathione S-transferase, OATP2, and MDR1 [19; 25]. Therefore, PXR plays a role in the regulation of many physiological and pathological processes in the liver, such as the metabolism of drugs, bile acids, and cholesterol, but has also been involved in molecular pathways triggering inflammation and cancer [19; 25]. Hence, since PXR is responsible for controlling the transcription of genes involved in fibrogenesis, inflammation, and cell proliferation, many efforts have been addressed to unravel its role in the development of chronic liver diseases, a broad spectrum of different dysfunctions variable both for etiologies and pathological features. Several pieces of evidence of PXR regulation and activity have been obtained in these contexts, although sometimes controversial and disease specific.