Abstract
The liver X receptor (LXR) and constitutive androstane receptor (CAR) are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. Here we show that LXRα and CAR are functionally related in vivo. Loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation; whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. Conversely, a combined loss of LXR α and β increased the basal expression of xenobiotic CAR target genes; whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXRα and CAR was also observed in cell culture and reporter gene assays. LXRα, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor co-activators. Interestingly, although CAR competed with LXRα for co-activators, the constitutive activity and recruitment of co-activators was not required for CAR to suppress the activity of LXRα. In vivo chromatin immunoprecipitation (ChIP) assay showed that co-treatment of a CAR agonist compromised the LXR agonist responisve recruitpment of LXRα to Srebp-1c, whereas a LXR agonist inhibited the CAR agonist responisve recruitment of CAR to Cyp2b10. In conclusion, our results have revealed dual functions of LXRα and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis.
Footnotes
- Received March 10, 2010.
- Revision received June 30, 2010.
- Accepted June 30, 2010.
- The American Society for Pharmacology and Experimental Therapeutics