Extrahepatic cholestasis downregulates Oatp1 by TNF-alpha signalling without affecting Oatp2 and Oatp4 expression and sodium-independent bile salt uptake in rat liver.
Hepatic uptake of bile salts is mediated by sodium-dependent and sodium-independent transport systems. During extrahepatic cholestasis, both the function and the expression of the Na(+)/taurocholate cotransporting polypeptide (Ntcp) are downregulated. To test whether sodium-independent organic anion-transporting polypeptides are also affected by extrahepatic cholestasis, the function and expression of all three Oatps have been determined in common bile duct-ligated (CBDL) rats. Oatp1/Oatp1a1 protein mass remained unchanged after CBDL for 1 day, but then declined by 75+/-7% and 90+/-17%, respectively, after 3 and 7 days. In contrast, Oatp2/Oatp1a4 and Oatp4/Oatp1b2 protein expression was not affected by CBDL as compared with controls. After CBDL, Oatp1 mRNA was rapidly downregulated by 68+/-21% of untreated controls (P<0.05) within 24 h, and remained at similar levels at 3 and 7 days. Cytokine-inactivation studies with etanercept pretreatment demonstrated that TNF-alpha-dependent signals mediated the down-regulation of this transporter gene at both protein and mRNA levels during obstructive cholestasis. Sodium-independent uptake of taurocholate and cholate into freshly isolated hepatocyte suspensions showed neither significant differences in K(m) nor V(max) values. These results indicate that sodium-independent transport of bile salts may be mediated by Oatp2 and 4 during biliary obstruction, because its expression remains unaffected and may compensate for loss of Oatp1 expression and function in cholestatic hepatocytes.
Geier
Andreas
A
Department of Medicine III, University Hospital Aachen (UKA), Aachen University (RWTH), Aachen, Germany. ageier@ukaachen.de
Dietrich
Christoph G
CG
Trauner
Michael
M
Gartung
Carsten
C
D000818:Animals; D020355:Cholates / Q000378:metabolism*; D001651:Cholestasis, Extrahepatic / Q000378:metabolism*; D003135:Common Bile Duct / Q000601:surgery; D004195:Disease Models, Animal; D015536:Down-Regulation; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013656:Taurocholic Acid / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020355:Cholates; D007074:Immunoglobulin G; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C421102:Slco1a1 protein, rat; C503597:Slco1a4 protein, rat; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid; D012964:Sodium; D000068800:Etanercept