首页|The 3'-untranslated region contributes to the pregnane X receptor (PXR) expression down-regulation by PXR ligands and up-regulation by glucocorticoids
The 3'-untranslated region contributes to the pregnane X receptor (PXR) expression down-regulation by PXR ligands and up-regulation by glucocorticoids
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Pregnane X receptor (PXR) is the major regulator of xenobiotic metabolism.PXR itself is controlled by various signaling molecules including glucocorticoids.Moreover,negative feed-back regulation has been proposed at the transcriptional level.We examined the involvement of the 3'-untranslated region (3'-UTR) of NR1I2 mRNA and microRNAs in PXR-and glucocorticoid receptor (GR)-mediated regulation of NR1I2 gene expression.PXR ligands were found to significantly down-regulate NR1I2 mRNA expression in a set of 14 human hepatocyte cultures.Similarly,PXR was downregulated by PCN in the C57/BL6 mice liver.In mechanistic studies with the full-length 3'-UTR cloned into luciferase reporter or expression vectors,we showed that the 3'-UTR reduces PXR expression.From the miRNAs tested,miR-18a-5p inhibited both NR1I2 expression and CYP3A4 gene induction.Importantly,we observed significant upregulation of miR-18a-5p expression 6 h after treatment with the PXR ligand rifampicin,which indicates a putative mechanism underlying NR1I2 negative feed-back regulation in hepatic cells.Additionally,glucocorticoids upregulated NR1I2 expression not only through the promoter region but also via 3'-UTR regulation,which likely involves downregulation of miR-18a-5p.We conclude that miR-18a-5p is involved in the down-regulation of NR1I2 expression by its ligands and in the upregulation of NR1I2 mRNA expression by glucocorticoids in hepatic cells.
Gene expressionMicroRNAGlucocorticoidRegulationPregnane X receptorCytochrome P450 3A4
Tomas Smutny、Jan Dusek、Lucie Hyrsova、Jana Nekvindova、Alzbeta Horvatova、Stanislav Micuda、Sabine Gerbal-Chaloin、Petr Pavek
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Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University,Hradec Kralove CZ-500 05, Czech Republic
Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove CZ-500 05, Czech Republic
Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove CZ-500 03, Czech Republic
IRMB, INSERM, University Montpellier, Montpellier, France
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This work was supported by grants from the Czech Science Foundation 17-06841S to Petr Pavek and EFSA-CDNThis work was supported by grants from the Czech Science Foundation 17-06841S to Petr Pavek and EFSA-CDN
CZ.02.1.01/0.0/0.0/16_019/0000841Czech Republic co-funded by ERDF to Tomas Smutny
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