REGULATION OF HEPATOCYTE BILE-SALT TRANSPORTERS BY ENDOTOXIN AND INFLAMMATORY CYTOKINES IN RODENTS

Background & Alms: Pathophysiological conditions such as sepsis and he patitis are mediated by inflammatory cytokines and frequently are asso ciated with cholestasis. The aim of this study was to determine the ef fect of endotoxin (lipopolysaccharide [LPS]) and cytokine administrati on on hepatocellular transporters involved in bile salt transport. Met hods: LPS and cytokines were administered to Sprague-Dawley rats or C5 70L/6 mice, and the expression and function of hepatocyte transporters involved in bile salt secretion were examined. Results: LPS caused ge ne expression of the hepatocyte basolateral sodium-dependent taurochol ate cotransporter (Ntcp) to decrease by more than 90%. Tumor necrosis factor alpha (TNF-alpha) or interleukin (IK) 1 beta also produced a ti me-dependent decrease in Ntcp messenger RNA levels, whereas IL-6 had n o 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 up take. Activity of the hepatocyte basolateral Na+,K+-adenosine triphosp hatase (ATPase) was also decreased by 50% in a posttranslational manne r after endotoxin treatment. Conclusions: Endotoxin inhibits hepatocel lular sodium-dependent bile salt uptake by decreasing both expression of Ntcp and activity of the Na+, K+-ATPase. The effects on Ntcp are me diated via TNF-alpha and IL-1 beta. Alterations of these transporters may contribute to the cholestasis of sepsis and inflammation.