Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy
Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy
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DOI：
10.1016/j.jhep.2010.11.023
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发表时间：
2011-08-01
影响因子：
25.7
通讯作者：
Tsuchida, Shigeki
中科院分区：
文献类型：
--
作者：
Miura, Takuya;Kimura, Norihisa;Tsuchida, Shigeki
背景与目的：为了阐明大规模肝切除术后持续性胆汁淤积的机制，在大鼠模型中探讨这种胆汁淤积与胆汁酸有机阴离子转运蛋白的表达和定位之间的关系。方法：对雄性Sprague-Dawley大鼠进行90%肝切除，在第0、1、3和7天收获组织进行微阵列分析、实时定量聚合酶链反应（RT-PCR）。 Western blotting和免疫组织化学检测多药耐药蛋白4（Mrp4）、胆汁盐输出泵（Bsep）和钠依赖性牛磺胆酸共转运多肽（Ntcp）的表达。结果：第3天和第7天观察到血清胆汁酸水平持续升高。RT-PCR和Western blotting表明位于基底外侧膜的胆汁酸输出泵Mrp4的表达在第3天和第7天增加。 3. Ntcp（一种用于从血窦摄取胆汁酸的转运蛋白）的表达在此期间显着下降。 Bsep（一种位于小管膜的输出泵）的水平没有变化。免疫组织化学揭示了 Mrp4 和 Bsep 分别定位在基底外侧膜和小管膜中。另一方面，在第 3 天和第 7 天，Ntcp 定位于细胞质中，在基底外侧膜中几乎检测不到。结论：这些结果表明 Ntcp 的持续抑制和易位以及基底外侧膜上 Mrp4 的表达似乎是大规模肝切除术后血液胆汁酸水平升高的原因。 (C) 2010 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model.Methods: Male Sprague-Dawley rats were subjected to 90% hepatectomy, and tissues were harvested at 0, 1, 3, and 7 days for microarray analysis, quantitative real-time polymerase chain reaction (RT-PCR). Western blotting, and immunohistochemistry to examine the expression of multidrug resistance protein 4 (Mrp4), bile salt export pump (Bsep), and sodium-dependent taurocholate cotransporting polypeptide (Ntcp).Results: Persistently elevated levels of serum bile acids were observed at days 3 and 7. RT-PCR and Western blotting indicated that the expression of Mrp4, a bile acid export pump located in the basolateral membrane, was increased at day 3. The expression of Ntcp, a transporter used to uptake bile acids from the sinusoids, was significantly decreased throughout the period. The levels of Bsep, an export pump localized to the canalicular membrane, were unchanged. Immunohistochemistry revealed the localization of Mrp4 and Bsep in the basolateral and canalicular membranes, respectively. On the other hand, at days 3 and 7. Ntcp was localized in the cytoplasm and was hardly detected in the basolateral membrane.Conclusions: These results suggested that the sustained repression and translocation of Ntcp and the expression of Mrp4 at the basolateral membrane seem to be responsible for the high blood bile acids levels after massive hepatectomy. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.