Targeting xenobiotic receptors PXR and CAR for metabolic diseases

Abstract

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.

Figure 1. PXR and CAR as potential therapeutic targets for metabolic diseases

Activation of CAR suppresses both hepatic gluconeogenesis and lipogenesis, likely mediated through its inhibitory effect on transcriptional factors such as FoxO1, HNF4α, PGC1α, LXR, and SREBP1. Targeting both gluconeogenic and lipogenic pathways by CAR confers its desired properties as a promising therapeutic target for metabolic diseases. The in vivo benefit of CAR activation in relieving metabolic disease has also been reported. In the liver, PXR has a similar inhibitory effect on gluconeogenesis. However, PXR activation may increase fatty acid influx and lipogenesis directly or by activating PPARγ, and suppress fatty acid oxidation through suppressing FoxA2. PXR activation also has immunosuppressive effects evidenced in the liver, intestine, and immune cells. The in vivo significance of PXR in metabolic syndrome remains to be demonstrated. CAR; constitutive androstane receptor; PXR, pregnane X receptor; FoxO1, Forkhead box protein O1; HNF4α, hepatocyte nuclear factor 4α; LXR, liver X receptor; SREBP1, sterol regulatory element-binding protein 1; PPARγ, peroxisome proliferator-activated receptor γ; FoxA2, forkhead box protein A2.