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Extrahepatic cholestasis downregulates Oatp1 by TNF‐α signalling without affecting Oatp2 and Oatp4 expression and sodium‐independent bile salt uptake in rat liver
Author(s) -
Geier Andreas,
Dietrich Christoph G.,
Trauner Michael,
Gartung Carsten
Publication year - 2007
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2007.01523.x
Subject(s) - cholestasis , bile salt export pump , medicine , bile acid , organic anion transporter 1 , hepatocyte , endocrinology , chemistry , sodium , biology , transporter , biochemistry , gene , organic chemistry , in vitro
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‐α‐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.