Xenoreceptors CAR and PXR Activation and Consequences on Lipid Metabolism, Glucose Homeostasis, and Inflammatory Response

Abstract

Xenobiotic and drug metabolism and transport are managed by a large number of genes coordinately regulated by at least three nuclear receptors or xenosensors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR, NR1I3), and pregnane X receptor (PXR, NR1I2). Initially characterized as xenosensors, it is now evident that CAR and PXR also trigger pleiotropic effects on liver function. Recent studies have shown the existence of crosstalk between xenosensors and other nuclear receptors or transcription factors controlling endogenous signaling pathways which regulate physiological functions. This review is focused on recent observations showing that activation of CAR and PXR alters lipid metabolism, glucose homeostasis, and inflammation by interfering with HNF4alpha, FoxO1, FoxA2, PGC1alpha, or NFkB p65. Such crosstalks explain clinical observations and provide molecular mechanisms allowing understanding how xenobiotics and drugs may affect physiological functions and provoke endocrine disruptions.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…Accordingly, we have observed that high DEHP exposure (1100 mg/Kg/day for 2 weeks) led to a significant reduction in plasma total T4 (data not shown). CAR and PXR are also increasingly recognized as important regulators of genes involved in lipid and glucose homeostasis (for review: [70,71]. In particular, CAR activation reduces the expression of critical genes involved in fatty acid oxidation [72], bile acid synthesis and gluconeogenesis [73].…”

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

“…CAR and PXR are nuclear receptors that regulate genes involved in important physiological pathways including xenobiotic, glucose, and fatty acid metabolism (Maglich et al, 2002;Moreau et al, 2007;Konno et al, 2008). CAR and PXR have been also shown to modulate the immune response and the genes involved in lipid and cholesterol synthesis (Moreau et al, 2007;Roth et al, 2008).…”

“…CAR and PXR have been also shown to modulate the immune response and the genes involved in lipid and cholesterol synthesis (Moreau et al, 2007;Roth et al, 2008). No definite physical ligand have been identified for both CAR and PXR, but previous reports show they exhibit the ability to bind multiple ligands (Tzameli et al, 2000;Sueyoshi and Negishi, 2001;Willson and Kliewer, 2002;Maglich et al, 2003).…”

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

“…RXRα influences a variety pathways because of its ability to activate transcription of target genes as a homodimer or as an obligate partner of other nuclear receptors, such as pregnane X receptor (PXR or NR1I2) and constitutive androstane receptor (CAR or NR1I3) (5,7). PXR and CAR were originally identified as xenosensors that regulate the expression of drug-metabolizing enzymes/transporters (Phase I, II and III); however, recent studies have shown that they also affect other metabolic pathways, such as lipid homeostasis and metabolism (8,9).…”