RRC ID 69057
Author Shizu R, Ezaki K, Sato T, Sugawara A, Hosaka T, Sasaki T, Yoshinari K.
Title PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α.
Journal Cells
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.
Volume 10(12)
Published 2021-12-16
DOI 10.3390/cells10123550
PII cells10123550
PMID 34944058
PMC PMC8700377
MeSH Gene Expression Regulation Hep G2 Cells Hepatocytes / metabolism Hepatocytes / pathology Humans Hydroxymethylglutaryl-CoA Synthase / genetics* Liver / metabolism PPAR alpha / genetics* Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics* Pregnane X Receptor / genetics* Promoter Regions, Genetic / genetics Transcription, Genetic / genetics Xenobiotics / metabolism
IF 4.366
Human and Animal Cells COS-1(RCB0143) Hep G2(RCB1886)