Nuclear receptor PXR, transcriptional circuits and metabolic relevance

Abstract

The pregnane X receptor (PXR, NR1I2) is a ligand activated transcription factor that belongs to the nuclear hormone receptor (NR) superfamily. PXR is highly expressed in the liver and intestine, but low levels of expression have also been found in many other tissues. PXR plays an integral role in xenobiotic and endobiotic metabolism by regulating the expression of drug metabolizing enzymes and transporters, as well as genes implicated in the metabolism of endobiotics. PXR exerts its transcriptional regulation by binding to its DNA response elements as a heterodimer with the retinoid X receptor (RXR) and recruitment of a host of coactivators. The biological and physiological implications of PXR activation are broad, ranging from drug metabolism and drug-drug interactions to the homeostasis of numerous endobiotics, such as glucose, lipids, steroids, bile acids, bilirubin, retinoic acid, and bone minerals. The purpose of this article is to provide an overview on the transcriptional circuits and metabolic relevance controlled by PXR.

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

“…Threonine-290 Regulates Human PXR Nuclear Translocation Discussion PXR, a member of the nuclear receptor superfamily, was originally characterized as a xenobiotic-activated transcription factor that plays a key role in regulating the expression of genes encoding drugmetabolizing enzymes and drug transporters. It was subsequently found to potentiate various biologic effects associated with pharmacologic and toxicologic consequences-not only the metabolism and clearance of endobiotics and xenobiotics, including various therapeutic drugs and environmental endocrine disruptors, but also cancer pathogenesis (Timsit and Negishi, 2007;Staudinger and Lichti, 2008;Ihunnah et al, 2011;Pondugula and Mani, 2013) and hepatic energy metabolism including gluconeogenesis, the b-oxidation of fatty acids, and lipogenesis (Konno et al, 2008). PXR is activated by the binding of endogenous and exogenous xenobiotics to its ligand-binding domain and is then translocated to the nucleus in which it activates transcription by binding to the xenobiotic-response element in the promoter region of the target gene with RXR (Timsit and Negishi, 2007).…”

Pregnane X Receptor in Drug Development

“…Bile acids play major roles in cholesterol metabolism and excretion. They are produced in the liver by CYPs-mediated oxidation of cholesterol (Ihunnah et al 2011). Accumulation of bile acid is mainly responsible for cholestatic liver injury (Allen et al 2011).…”

Roles of Xenobiotic Receptors in Vascular Pathophysiology

“…The PXR-regulated target genes involving these processes include metabolizing enzymes such as CYP3A11, SULT2A, the transporter multidrug resistance-associated protein3 (MRP3), organic anion transporting polypeptide (OATP2), solute carrier organic anion transporter family member 1B1 (SLCO1B1), adenosine triphosphate (ATP)-binding cassette subfamily B 11 (ABCB11), ATP-binding cassette subfamily C2 (ABCC2) and CYP7A1. 17 78 Therefore, PXR and CAR may offer a target to effectively reduce bile acids and thus limit LDL cholesterol levels.…”

“…17 The circulation can be a hostile milieu, with increased concentrations of xenobiotics and endobiotics resulting from drugs, chemical agents, smoking, air pollution, nutritional metabolites, and pathogenic microbes or their toxins. 53 These circulating endogenous and foreign chemicals can contribute to vascular dysfunction and the development of vascular disease.…”