Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats
Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats
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DOI：
10.1124/dmd.32.7.734
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发表时间：
2004-07-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Cherrington, NJ;Slitt, AL;Klaassen, CD
肝转运蛋白的功能是将有机物穿过窦膜和小管膜。在肝外胆汁淤滞期间，参与物质从血液到胆汁运动的转运蛋白，如钠/牛磺胆酸共转运多肽（Ntcp）和多药耐药蛋白2 (Mrp2)，下调，而其他从肝脏到血液运输化学物质的转运蛋白，如Mrp3，上调。与转运蛋白表达响应胆汁成分积聚压力的肝外胆汁淤积不同，脂多糖（LPS）诱导的肝内胆汁淤积可能由转运蛋白表达的改变直接引起。本研究的目的是定量确定LPS对转运蛋白表达的影响，并研究LPS改变Sprague-Dawley大鼠肝脏主要转运蛋白mRNA水平的机制。肝脏Mrp2、Mrp6、多重耐药蛋白1a （Mdr1a）、有机阴离子转运多肽1 （Oatp1）、Oatp2、Oatp4、Ntcp、胆盐出口泵、有机阳离子转运蛋白1 （Oct1）和有机阴离子转运蛋白3 (Oat3) mRNA水平在LPS处理后约6小时开始显著降低，而Mrp5和Oat2水平不变。相比之下，LPS增加了Mrp1， Mrp3和Mdr1b的mRNA水平，同时下调了转运蛋白。地塞米松预处理可以减少细胞因子的释放，逆转LPS处理后Mdr1a、Oatp1、Oatp2、Oct1和Ntcp mRNA的减少。此外，地塞米松预处理也阻止了lps介导的Mrp1、Mrp3和Mdr1b的增加，而氨基胍或氯化钆预处理（一种诱导性一氧化氮合成酶抑制剂和一种库普弗细胞毒物）对lps诱导的变化没有影响。多种转运蛋白的同时抑制和诱导，以及地塞米松对lps介导的抑制和诱导的抑制作用，表明这些反应可能是通过类似的途径介导的。
The function of hepatic transporters is to move organic substances across sinusoidal and canalicular membranes. During extrahepatic cholestasis, transporters involved in the movement of substances from blood to bile, such as sodium/taurocholate-cotransporting polypeptide (Ntcp) and multidrug resistance protein 2 (Mrp2), are down-regulated, whereas others that transport chemicals from liver to blood, such as Mrp3, are up-regulated. Unlike extrahepatic cholestasis, where transporter expression responds to the stress of accumulating bile constituents, lipopolysaccharide (LPS)-induced intrahepatic cholestasis may be directly caused by alterations in transporter expression. The aim of this study was to quantitatively determine the effect of LPS on transporter expression and study the mechanism(s) by which LPS alters mRNA levels of major hepatic transporters in Sprague-Dawley rats. Hepatic mRNA levels of Mrp2, Mrp6, multiple drug resistance protein 1a (Mdr1a), organic anion-transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, Ntcp, bile salt export pump, organic cation transporter 1 (Oct1), and organic anion transporter 3 (Oat3) were dramatically decreased, beginning approximately 6 h after LPS administration, whereas Mrp5 and Oat2 levels were unchanged. In contrast, LPS increased mRNA levels of Mrp1, Mrp3, and Mdr1b concurrently with the down-regulated transporters. Pretreatment with dexamethasone, which decreases the release of cytokines, reversed the reduction of Mdr1a, Oatp1, Oatp2, Oct1, and Ntcp mRNA following LPS administration. Furthermore, dexamethasone pretreatment also prevented the LPS-mediated increase in Mrp1, Mrp3, and Mdr1b, whereas pretreatment with aminoguanidine or gadolinium chloride, an inhibitor of inducible nitric oxide synthetase and a Kupffer cell toxicant, respectively, had no effect on the LPS-induced changes. The concurrent repression and induction of various transporters, as well as dexamethasone abatement of both LPS-mediated repression and induction, indicates that these responses may be mediated through similar pathways.