Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

Abstract

The pregnane X receptor (PXR, NR1I2) is a nuclear receptor which exerts its regulatory function by heterodimerization with the retinoid-X-receptor α (RXRα, NR2B1) and binding to the promoter and enhancer regions of diverse target genes. PXR is involved in the regulation of drug metabolism and excretion, metabolic and immunological functions and cancer pathogenesis. PXR activity is strongly regulated by the association with coactivator and corepressor proteins. Coactivator proteins exhibit histone acetyltransferase or histone methyltransferase activity or associate with proteins having one of these activities, thus promoting chromatin decondensation and activation of the gene expression. On the contrary, corepressor proteins promote histone deacetylation and therefore favor chromatin condensation and repression of the gene expression. Several studies pointed to clear cell- and ligand-specific differences in the activation of PXR. In this article, we will review the critical role of coactivator and corepressor proteins as molecular determinants of the specificity of PXR-mediated effects. As already known for other nuclear receptors, understanding the complex mechanism of PXR activation in each cell type and under particular physiological and pathophysiological conditions may lead to the development of selective modulators with therapeutic potential.

Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human RORγT Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity

“…This difference might be explained by the off-target proteins interacting with each of the analyzed compounds or by their ability to recruit different coactivators or corepresors and/or binding to different response elements in the regulatory sites as was evidenced previously for PXR ligands, e.g., bisphenol A, phthalate, or pregnenolone, which induced PXR-dependent CYP3A4 but not ABCB1. Interestingly, cisplatin induced much more expression of ABCB1 in comparison to CYP3A4 [48,49]. Chromatin immunoprecipitation also confirmed that ursolic, corosolic, and oleanolic acids decrease the binding of RORγT from the promoters of the IL17A and IL17F genes (Figure 9).…”

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

“…Activation of PPARα and PPARγ (Li, Guo, & Wu, 2021; Zhang et al, 2014) by pharmaceutical agents, endogenous compounds and PFAS has been well‐studied (Table 3). Important for the AOP network, PPARα (Oshida, Vasani, Thomas, et al, 2015), PXR (Rigalli et al, 2021), and CAR (Ding et al, 2006) are activated in response to caloric restriction or fasting. Placental PPARγ has been shown to be downregulated by PFOS (Li, Quan, Lei, et al, 2021), triclosan (Li, Quan, Zhang, et al, 2021), and lipopolysaccharide (Fu et al, 2019) in mouse placenta and human trophoblast cultures.…”

“…The roles of CAR and PXR in hepatic energy metabolism have been reviewed (Konno et al, 2008; Kublbeck et al, 2020; Rigalli et al, 2021). These nuclear receptors decrease energy metabolism by down‐regulating gluconeogenesis, fatty acid oxidation and ketogenesis, and upregulating lipogenesis.…”