Targeting xenobiotic receptors PXR and CAR for metabolic diseases

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two closely related and liver-enriched nuclear hormone receptors originally defined as xenobiotic receptors. Recently, an increasing body of evidence suggests that PXR and CAR also have endobiotic functions that impact glucose and lipid metabolism, as well as the pathogenesis of metabolic diseases. These new findings suggest that PXR and CAR not only regulate the transcription of drug-metabolizing enzymes and transporters, but also orchestrate energy metabolism and immune responses to accommodate stresses caused by xenobiotic exposures. The effectiveness of targeting PXR and CAR in the treatment of metabolic disorders, such as obesity, type 2 diabetes (T2D), dyslipidemia, and atherosclerosis, have been suggested in animal models. However, translation of these basic research results into clinical applications may require further investigation to determine the human relevance, and to obtain better understanding of the mechanisms through which PXR and CAR affect energy metabolism. Given a wide variety of natural or synthetic compounds that are PXR and CAR modulators, it is hoped that these two ‘xenobiotic receptors’ can be harnessed for therapeutic potentials in managing metabolic diseases.