Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor
Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor
复制标题
DOI：
10.1016/j.toxlet.2016.11.013
复制
发表时间：
2017-01-04
影响因子：
3.5
通讯作者：
Pavek, Petr
中科院分区：
文献类型：
--
作者：
Carazo, Alejandro;Hyrsova, Lucie;Pavek, Petr
孕烷X（PXR）、维生素D（VDR）和法尼醇X（FXR）核受体已被证明是控制胆汁酸解毒或合成的胆汁酸受体。鹅去氧胆酸（CDCA）和石胆酸（LCA）分别是FXR和VDR的配体，而LCA的3-酮基和乙酰化衍生物已被描述为这三种受体的配体。通过解毒酶或微生物组对胆汁酸（脱氧胆酸）、LCA、CA（胆酸）和CDCA的结合可能对与胆汁酸核受体的相互作用有影响。我们采用HepG 2细胞报告基因分析、重组PXR的TR-FRET分析和RT-PCR研究了乙酰化胆汁酸和酮基胆汁酸对分化的HepaRG细胞核受体激活及其靶基因表达的影响，证明了DCA 3，12-二乙酸酯和CA 3，7，12-三乙酸酯衍生物是PXR和DCA 3的配体，12-diacetate可诱导PXR靶基因如CYP 3A 4、CYP 2B 6和ABCB 1/MDR 1的表达。乙酰化胆汁酸衍生物是否是PXR的新型内源性配体，具有解毒或生理功能，有待进一步研究。(C)2016爱思唯尔爱尔兰有限公司版权所有。
The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors.In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells.We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1.In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments. (C) 2016 Elsevier Ireland Ltd. All rights reserved.