Abstract
Background: PXR is a xenobiotic-responsive nuclear receptor that controls the expression of drug-metabolizing enzymes. Drug-induced activation of PXR sometimes causes drug–drug interactions due to the induced metabolism of co-administered drugs. Our group recently reported a possible drug–drug interaction mechanism via an interaction between the nuclear receptors CAR and PPARα. As CAR and PXR are structurally and functionally related receptors, we investigated possible crosstalk between PXR and PPARα. Methods: Human hepatocyte-like HepaRG cells were treated with various PXR ligands, and mRNA levels were determined by quantitative reverse transcription PCR. Reporter assays using the HMGCS2 promoter containing a PPARα-binding motif and mammalian two-hybrid assays were performed in HepG2 or COS-1 cells. Results: Treatment with PXR activators reduced the mRNA levels of PPARα target genes in HepaRG cells. In reporter assays, PXR suppressed PPARα-dependent gene expression in HepG2 cells. In COS-1 cells, co-expression of PGC1α, a common coactivator of PPARα and PXR, enhanced PPARα-dependent gene transcription, which was clearly suppressed by PXR. Consistently, in mammalian two-hybrid assays, the interaction between PGC1α and PPARα was attenuated by ligand-activated PXR. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment.
Highlights
Xenobiotic-sensing nuclear receptors, PXR and CAR, which are encoded by NR1I2 and NR1I3, respectively, play crucial roles in the induction of drug-metabolizing enzymes and drug transporters in the liver [1,2]
To investigate the influence of treatment with PXR-activating drugs on PPARα target gene expression, human hepatocyte-like HepaRG cells were treated with rifampicin, rifaximin, simvastatin, or SR12813, and the mRNA levels were quantified (Figure 1)
In a reporter assay using HepG2 cells and the promoter sequence of HMGCS2 containing a PPARα binding motif, wild type PXR clearly prevented PPARα-dependent gene transcription, but no inhibition was observed with a PXR mutant lacking the coactivatorinteracting AF2 domain, suggesting the involvement of coactivator interaction in the PXR-mediated suppression of transcription by PPARα
Summary
Xenobiotic-sensing nuclear receptors, PXR and CAR, which are encoded by NR1I2 and NR1I3, respectively, play crucial roles in the induction of drug-metabolizing enzymes and drug transporters in the liver [1,2]. These nuclear receptors share target genes and cooperate in the detoxification of harmful xenobiotics. The activation of these receptors by drugs or food ingredients results in the enhanced metabolism and excretion of coadministered drugs, so these receptors are mainly responsible for drug–drug interactions (DDIs) or drug-food interactions. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment
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