The nuclear receptors PXR and LXR are regulators of the scaffold protein PDZK1

被引:6
作者
Ferreira, Celio [1 ]
Meyer, Ramona [1 ]
zu Schwabedissen, Henriette E. Meyer [1 ]
机构
[1] Univ Basel, Dept Pharmaceut Sci, Biopharm, CH-4056 Basel, Switzerland
来源
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS | 2019年 / 1862卷 / 04期
基金
瑞士国家科学基金会;
关键词
Scaffold protein; PDZ domain; PDZK1; LXR; PXR; HDL; PREGNANE-X-RECEPTOR; DENSITY-LIPOPROTEIN RECEPTOR; HEPATIC SCAVENGER RECEPTOR; B TYPE-I; SR-BI; CHOLESTEROL TRANSPORT; SURFACE LOCALIZATION; LIPID-METABOLISM; LIVER; DOMAIN;
D O I
10.1016/j.bbagrm.2019.02.007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PDZK1 (NHERF3) interacts with membrane proteins whereby modulating their spatial arrangement, membrane stability, and function. One of the membrane proteins shown to be stabilized by interaction with PDZK1 is the HDL-receptor SR-BI (SCARB1). Testing the influence of TO 901317, a known activator of liver X receptor alpha (LXR alpha, NR1H3) which is a central regulator of the lipid homeostasis, Grefhorst et al. reported in 2012 that administration of TO 901317 did not affect PDZK1 expression and reduced the amount of SR-BI protein in mouse liver. Considering that TO 901317 also activates the xenosensor pregnane X receptor (PXR, NR1I2), it was aim of this study to further investigate the influence of LXR alpha and PXR activation on transcription of PDZK1. First, we tested the transactivation of PDZK1 by LXR alpha or PXR in cell-based reporter gene assays comparing the effect of prototypical ligands to that of TO 901317. Ligand mediated activation of LXR alpha increased, while that of PXR lowered luciferase activity. Further, we located the most likely binding site for LXR alpha and PXR on the PDZK1 promoter between -85 bp and -54 bp. The transcriptional regulation by LXR alpha was further supported showing enhanced mRNA expression of PDZK1 in HepG2 cells treated with the selective LXR alpha-agonist GW3965, while treatment with TO 901317 reduced the protein amount of PDZK1. Taken together, we provide evidence that both LXR alpha and PXR are transcriptional regulators of PDZK1 supporting the previous notion that the scaffold protein is part of cholesterol homeostasis and drug metabolism.
引用
收藏
页码:447 / 456
页数:10
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