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. On the other hand, 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 coactivators. Interestingly, although CAR competed with LXRα for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXRα. In vivo chromatin immunoprecipitation assay showed that cotreatment of a CAR agonist compromised the LXR agonist responsive recruitment of LXRα to Srebp-1c, whereas an LXR agonist inhibited the CAR agonist-responsive 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
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES014626]; the National Institute of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK076962]; and the National Natural Science Foundation of China [Grant 30870926].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.064618.
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ABBREVIATIONS:
- LXR
- liver X receptor
- CAR
- constitutive androstane receptor
- LXRE
- liver X receptor-responsive element
- PXR
- pregnane X receptor
- PBRE
- phenobarbital response element
- Acc-1
- acetyl CoA carboxylase 1
- Fas
- fatty acid synthase
- Scd-1
- stearoyl CoA desaturase-1
- SRC1
- steroid receptor coactivator 1
- PCR
- polymerase chain reaction
- Srebp-1c
- sterol regulatory element-binding protein 1c
- TO1317 (TO901317)
- N-methyl-n-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-phenyl]-benzenesulfonamide
- TCPOBOP
- 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene
- VP
- viral protein 16
- ChIP
- chromatin immunoprecipitation
- GW3965
- 3-[3-[[[2-chloro-3-(trifluoromethyl)phenyl]methyl](2,2-diphenylethyl)amino]propoxy]benzeneacetic acid hydrochloride
- GST
- glutathione transferase
- DMSO
- dimethyl sulfoxide
- β-gal
- β-galactoside
- tk
- thymidine kinase
- DKO
- double knockout
- DR-4
- direct repeat spaced by four nucleotides
- PPAR
- peroxisome proliferator-activated receptor
- RXR
- retinoid X receptor
- HA
- hemagglutinin
- HDL
- high-density lipoprotein
- AF
- activator function
- BRL49653
- rosiglitazone.
- Received March 10, 2010.
- Accepted June 30, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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