The 3'-untranslated region contributes to the pregnane X receptor (PXR) expression down-regulation by PXR ligands and up-regulation by glucocorticoids

• 来源期刊: 药学学报（英文版）
• 关键词: Gene expression MicroRNA Glucocorticoid Regulation Pregnane X receptor Cytochrome P450 3A4
• 年，卷（期）: 2020,（1）
• 页码范围: 136-152
• 页数: 17页
• 语种: 英文

摘要

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.