Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase-signaling pathway.
Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase-signaling pathway.
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人梗阻性胆汁淤积中肝多药耐药相关蛋白 3/ATP 结合盒亚家族 C 3 表达升高是通过肿瘤坏死因子 α 和 c-Jun NH2 末端激酶/应激激活蛋白激酶信号通路介导的。
DOI：
10.1002/hep.24801
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发表时间：
2012-05
期刊：
影响因子：
13.5
通讯作者：
Chen, Wensheng
中科院分区：
文献类型：
--
作者：
Chai, Jin;He, Yu;Cai, Shi-Ying;Jiang, Zhongyong;Wang, Huaizhi;Li, Qiong;Chen, Lei;Peng, Zhihong;He, Xiaochong;Wu, Xiaoping;Xiao, Tianli;Wang, Rongquan;Boyer, James L.;Chen, Wensheng
多药耐药相关蛋白3 （MRP3, ABCC3）通过分泌一系列有毒的有机阴离子偶联物，包括胆汁盐，在保护肝细胞和其他组织中发挥重要作用。MRP3/ABCC3在一些胆汁淤积症患者的肝脏中表达升高，但这种上调的分子机制尚不清楚。在本报告中，我们评估了因胆管结石阻塞导致的梗阻性胆汁淤积患者（n=22）和非胆汁淤积患者对照（n=22）的肝脏MRP3/ABCC3表达。这些胆汁淤积症患者MRP3/ABCC3 mRNA和蛋白表达分别显著升高3.4倍和4.6倍，血浆TNFα升高4.7倍（P<0.01），肝脏SP1和LRH-1表达升高（mRNA水平分别为3.1倍和2.1倍，蛋白水平分别为3.5倍和2.5倍）。在这些患者中，肝脏MRP3/ABCC3 mRNA表达的诱导与血浆TNFα水平呈显著正相关。在HepG2细胞中，TNFα处理以剂量和时间依赖的方式诱导SP1和MRP3/ABCC3表达，其中JNK/SAPK磷酸化也被检测到增加。这些诱导在JNK抑制剂SP600125的存在下显著降低。EMSA显示，TNFα处理增强了HepG2细胞核提取物与MRP3/ABCC3启动子的结合活性，但被SP600125破坏。通过supershift EMSA检测，在胆汁淤积症患者的肝脏样本中也发现了MRP3/ABCC3启动子（主要由SP1组成）核蛋白结合活性的增加。我们的研究结果表明，在人类阻塞性胆汁淤积症中，肝脏MRP3/ABCC3表达的上调可能是由TNFα触发的，由JNK/SAPK和SP1的激活介导。
Multidrug resistance-associated protein 3 (MRP3, ABCC3) plays an important role in protecting hepatocytes and other tissues by excreting an array of toxic organic anion conjugates, including bile salts. MRP3/ABCC3 expression is increased in the liver of some cholestatic patients, but the molecular mechanism of this up-regulation remains elusive. In this report, we assessed liver MRP3/ABCC3 expression in patients (n=22) with obstructive cholestasis due to gallstones blockage of bile ducts and non-cholestatic patient controls (n=22). MRP3/ABCC3 mRNA and protein expression were significantly increased 3.4- and 4.6- fold, respectively in these cholestatic patients where elevated plasma TNFα (4.7-fold, P<0.01) and hepatic SP1 and LRH-1 expression (3.1- and 2.1-fold at mRNA level, 3.5- and 2.5-fold at protein level, respectively) were also observed. The induction of hepatic MRP3/ABCC3 mRNA expression is significantly positively correlated with the level of plasma TNFα in these patients. In HepG2 cells, TNFα treatment induced SP1 and MRP3/ABCC3 expression in a dose- and time-dependent manner, where increased phosphorylation of JNK/SAPK was also detected. These inductions were significantly reduced in the presence of the JNK inhibitor SP600125. TNFα treatment enhanced HepG2 cell nuclear extract binding activity to the MRP3/ABCC3 promoter, but was abolished by SP600125 as demonstrated by EMSA. An increase in nuclear protein binding activity to the MRP3/ABCC3 promoter consisting primarily of SP1 was also seen in liver samples from cholestatic patients as assessed by supershift EMSA assays. Our findings indicate that up-regulation of hepatic MRP3/ABCC3 expression in human obstructive cholestasis is likely triggered by TNFα, mediated by activations of JNK/SAPK and SP1.
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DOI：
10.1152/ajpgi.00191.2006
发表时间：
2007-05-01
影响因子：
4.5
作者：
Chen, Wensheng;Cai, Shi-Ying;Boyer, James L.
通讯作者：
Boyer, James L.
影响因子：
7.3
作者：
Teng, S.;Piquette-Miller, M.
通讯作者：
Piquette-Miller, M.
影响因子：
11
作者：
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Huang, JD
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25.7
作者：
Zelcer, N;van de Wetering, K;Borst, P
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Borst, P
影响因子：
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作者：
Sroka, Isis C.;Nagle, Raymond B.;Bowden, G. Tim
通讯作者：
Bowden, G. Tim