Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.
OBJECTIVE
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 C57BL/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 (IL) 1beta 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-1beta. Alterations of these transporters may contribute to the cholestasis of sepsis and inflammation.
Green
R M
RM
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. USA.
Beier
D
D
Gollan
J L
JL
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002779:Cholestasis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000009:adverse effects*; D015870:Gene Expression; D018836:Inflammation Mediators / Q000009:adverse effects*; D007375:Interleukin-1 / Q000009:adverse effects; D015850:Interleukin-6 / Q000009:adverse effects; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D027981:Symporters; D013656:Taurocholic Acid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D014409:Tumor Necrosis Factor-alpha; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D000254:Sodium-Potassium-Exchanging ATPase