Donner Markus G, Warskulat Ulrich, Saha Nirmalendu, Häussinger Dieter
Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, D-40225 Düsseldorf, Germany.
Biol Chem. 2004 Mar-Apr;385(3-4):331-9. doi: 10.1515/BC.2004.029.
Lipopolysaccharide (LPS) induces hepatocellular down-regulation and endocytic retrieval of multidrug resistance protein 2 (Mrp2, Abcc2). Basolateral Mrp isoforms may compensate for the intracellular metabolic changes in cholestasis. Therefore, the effect of LPS on the zonal localization of Mrp2 and Mrp3 and the expression of Mrp3, Mrp4, Mrp5, and Mrp6 mRNA were investigated in rat liver. In normal rat liver Mrp3 was found in pericentral hepatocytes also expressing glutamine synthetase. In LPS-treated rat liver the decrease in Mrp2 protein was most pronounced in pericentral hepatocytes, with only minor down-regulation in periportal hepatocytes. Conversely, induction of Mrp3 was found in pericentral hepatocytes with a low expression of Mrp2. Furthermore, we found a strong induction of Mrp5 mRNA. Likewise, Mrp6 mRNA was up-regulated, however Mrp6 protein expression was not significantly altered. It is concluded that Mrp3 is inversely regulated to Mrp2 in a zonal pattern and may compensate for the LPS-induced loss of Mrp2 in the perivenous area. Induction of pericentral Mrp3 and up-regulation of Mrp5 mRNA may play an important role in the hepatocellular clearance of cholephilic substances and cyclic nucleotides accumulating after LPS treatment.
脂多糖（LPS）可诱导肝细胞下调并通过内吞作用回收多药耐药蛋白2（Mrp2，Abcc2）。基底外侧的Mrp亚型可能会补偿胆汁淤积时的细胞内代谢变化。因此，研究了LPS对大鼠肝脏中Mrp2和Mrp3的区域定位以及Mrp3、Mrp4、Mrp5和Mrp6 mRNA表达的影响。在正常大鼠肝脏中，Mrp3存在于中央周围肝细胞中，这些细胞也表达谷氨酰胺合成酶。在LPS处理的大鼠肝脏中，Mrp2蛋白的减少在中央周围肝细胞中最为明显，而在门周肝细胞中仅有轻微下调。相反，在Mrp2低表达的中央周围肝细胞中发现了Mrp3的诱导。此外，我们发现Mrp5 mRNA有强烈诱导。同样，Mrp6 mRNA上调，但Mrp6蛋白表达没有明显改变。结论是，Mrp3在区域模式上与Mrp2呈反向调节，可能补偿LPS诱导的肝静脉周围区域Mrp2的缺失。中央周围Mrp3的诱导和Mrp5 mRNA的上调可能在LPS处理后肝细胞清除亲胆物质和积累的环核苷酸中起重要作用。
