Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents
Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents
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DOI：
10.1053/gast.1996.v111.pm8698199
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发表时间：
1996-07-01
期刊：
影响因子：
29.4
通讯作者：
Gollan, JL
中科院分区：
文献类型：
--
作者：
Green, RM;Beier, D;Gollan, JL
背景与优点：脓毒症、肝炎等病理生理状态是由炎性细胞因子介导的，常与胆汁淤积有关。本研究旨在探讨内毒素和细胞因子对参与胆盐转运的肝细胞转运蛋白的影响。方法：用脂多糖和细胞因子处理SD大鼠和C570L/6小鼠，观察肝细胞转运蛋白在胆盐分泌过程中的表达和功能。结果：脂多糖可使肝细胞钠依赖的牛磺胆酸转运蛋白基因表达下降90%以上。肿瘤坏死因子α或白介素1β也可引起Ntcp信使RNA水平的时间依赖性降低，而IL-6则没有影响。脂多糖可使肝细胞牛磺胆酸钠共转运体的基侧蛋白表达降低90%，并显著降低对牛磺胆酸钠的摄取。肝细胞底侧Na+，K+-三磷酸腺苷酶(ATPase)活性在内毒素处理后也下降了50%。结论：内毒素通过降低Ntcp表达和Na+，K+-ATPase活性，抑制肝细胞钠依赖胆盐摄取。对Ntcp的影响是通过TNF-α和IL-1β介导的。这些转运蛋白的改变可能导致败血症和炎症的胆汁淤积。
Background & Alms: Pathophysiological conditions such as sepsis and hepatitis are mediated by inflammatory cytokines and frequently are associated with cholestasis. The aim of this study was to determine the effect of endotoxin (lipopolysaccharide [LPS]) and cytokine administration on hepatocellular transporters involved in bile salt transport. Methods: LPS and cytokines were administered to Sprague-Dawley rats or C570L/6 mice, and the expression and function of hepatocyte transporters involved in bile salt secretion were examined. Results: LPS caused gene expression of the hepatocyte basolateral sodium-dependent taurocholate cotransporter (Ntcp) to decrease by more than 90%. Tumor necrosis factor alpha (TNF-alpha) or interleukin (IK) 1 beta also produced a time-dependent decrease in Ntcp messenger RNA levels, whereas IL-6 had no effect. LPS administration resulted in a concordant 90% reduction of basolateral protein expression of the hepatocyte sodium taurocholate cotransporter and markedly diminished sodium-dependent taurocholate uptake. Activity of the hepatocyte basolateral Na+,K+-adenosine triphosphatase (ATPase) was also decreased by 50% in a posttranslational manner after endotoxin treatment. Conclusions: Endotoxin inhibits hepatocellular sodium-dependent bile salt uptake by decreasing both expression of Ntcp and activity of the Na+, K+-ATPase. The effects on Ntcp are mediated via TNF-alpha and IL-1 beta. Alterations of these transporters may contribute to the cholestasis of sepsis and inflammation.