Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents

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.