Changes of Organic Anion Transporter MRP4 and Related Nuclear Receptors in Human Obstructive Cholestasis
Changes of Organic Anion Transporter MRP4 and Related Nuclear Receptors in Human Obstructive Cholestasis
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人梗阻性胆汁淤积中有机阴离子转运蛋白MRP4及相关核受体的变化
DOI：
10.1007/s11605-011-1473-2
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发表时间：
2011-06-01
影响因子：
3.2
通讯作者：
Chen, Wensheng
中科院分区：
文献类型：
--
作者：
Chai, Jin;Luo, Donglin;Chen, Wensheng
背景多药耐药相关蛋白4（Mrp 4）在啮齿类动物胆汁淤积性肝脏中的表达较低，但在胆汁淤积性肝脏中明显升高。核受体（NRs）是胆汁淤积模型中调节Mrp 4表达所必需的。然而，关于MRP 4和相关NR的信息，包括组成型雄烷受体（CAR），雌烷X受体（PXR）和维甲酸X受体-α（RXRα），在人类阻塞性胆汁淤积中相对缺乏。采用半定量RT-PCR、Western blot和免疫组化等方法检测梗阻性胆汁淤积症患者和非肝病患者肝组织中MRP 4、NR CAR、PXR和RXRα的表达。胆汁淤积组血清总胆汁酸（TBA）浓度与MRP 4蛋白表达呈显著正相关（P< 0.01）。梗阻性胆汁淤积患者PXR和RXRα mRNA/蛋白水平显著升高。CAR mRNA水平不变，而蛋白水平在梗阻性胆汁淤积中显著诱导。MRP 4 mRNA与CAR蛋白之间存在统计学正相关性（P< 0.05），表明CAR可能通过核转位激活MRP 4基因的转录。结论人阻塞性胆汁淤积症肝脏MRP 4水平显着升高，这可能通过增加肝细胞中有毒胆汁酸流出到血液中来减轻肝脏损伤。
BackgroundHepatic multidrug resistance-associated protein 4 (Mrp4) levels are low, but increase markedly in rodent cholestatic liver. Nuclear receptors (NRs) are essential for regulating Mrp4 expression in cholestasis models. However, information about MRP4 and related NRs, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoic X receptor-α (RXRα), is relatively lacking in human obstructive cholestasis. We collected liver samples from patients with obstructive cholestasis or without liver disease and investigated the expression of MRP4 and NRs CAR, PXR, and RXRα by semi-quantitative RT-PCR, Western blot and immunostaining assays.ResultsMRP4 mRNA/protein levels were markedly increased in obstructive cholestasis. Concentration of serum total bile acids (TBA) was significantly correlated with MRP4 protein in cholestasis samples (P< 0.01). PXR and RXRα mRNA/protein levels were significantly increased in obstructive cholestasis. CAR mRNA levels were unchanged while protein levels were markedly induced in obstructive cholestasis. There was a statistically positive correlation between MRP4 mRNA and CAR protein (P< 0.05), suggesting that CAR may activate transcription of MRP4 genes by its nuclear translocation.ConclusionHepatic MRP4 levels were dramatically induced in human obstructive cholestasis, which may reduce liver injury by increasing efflux of toxic bile acids from hepatocytes into blood.