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Slijepcevic, Davor; Kaufman, Christina; Wichers, Catharina G.K.; Gilglioni, Eduardo H.; Lempp, Florian A.; Duijst, Suzanne; de Waart, Dirk R.; Oude Elferink, Ronald P.J.; Mier, Walter; Stieger, Bruno; Beuers, Ulrich; Urban, Stephan; van de Graaf, Stan F.J.

Impaired uptake of conjugated bile acids and hepatitis b virus pres1‐binding in na+‐taurocholate cotransporting polypeptide knockout mice

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  • Media type: E-Article
  • Title: Impaired uptake of conjugated bile acids and hepatitis b virus pres1‐binding in na+‐taurocholate cotransporting polypeptide knockout mice
  • Contributor: Slijepcevic, Davor; Kaufman, Christina; Wichers, Catharina G.K.; Gilglioni, Eduardo H.; Lempp, Florian A.; Duijst, Suzanne; de Waart, Dirk R.; Oude Elferink, Ronald P.J.; Mier, Walter; Stieger, Bruno; Beuers, Ulrich; Urban, Stephan; van de Graaf, Stan F.J.
  • Published: Ovid Technologies (Wolters Kluwer Health), 2015
  • Published in: Hepatology, 62 (2015) 1, Seite 207-219
  • Language: English
  • DOI: 10.1002/hep.27694
  • ISSN: 0270-9139; 1527-3350
  • Origination:
  • University thesis:
  • Footnote:
  • Description: <jats:p>The Na<jats:sup>+</jats:sup>‐taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane of hepatocytes. It has recently been recognized as the receptor mediating hepatocyte‐specific entry of hepatitis B virus and hepatitis delta virus. Myrcludex B, a peptide inhibitor of hepatitis B virus entry, is assumed to specifically target NTCP. Here, we investigated BA transport and Myrcludex B binding in the first <jats:italic toggle="yes">Slc10a1</jats:italic>‐knockout mouse model (<jats:italic toggle="yes">Slc10a1</jats:italic> encodes NTCP). Primary <jats:italic toggle="yes">Slc10a1−/− </jats:italic> hepatocytes showed absence of sodium‐dependent taurocholic acid uptake, whereas sodium‐independent taurocholic acid uptake was unchanged. <jats:italic toggle="yes">In vivo</jats:italic>, this was manifested as a decreased serum BA clearance in all knockout mice. In a subset of mice, NTCP deficiency resulted in markedly elevated total serum BA concentrations, mainly composed of conjugated BAs. The hypercholanemic phenotype was rapidly triggered by a diet supplemented with ursodeoxycholic acid. Biliary BA output remained intact, while fecal BA excretion was reduced in hypercholanemic <jats:italic toggle="yes">Slc10a1−/− </jats:italic> mice, explained by increased <jats:italic toggle="yes">Asbt</jats:italic> and <jats:italic toggle="yes">Ostα/β</jats:italic> expression. These mice further showed reduced <jats:italic toggle="yes">Asbt</jats:italic> expression in the kidney and increased renal BA excretion. Hepatic uptake of conjugated BAs was potentially affected by down‐regulation of OATP1A1 and up‐regulation of OATP1A4. Furthermore, sodium‐dependent taurocholic acid uptake was inhibited by Myrcludex B in wild‐type hepatocytes, while <jats:italic toggle="yes">Slc10a1−/− </jats:italic> hepatocytes were insensitive to Myrcludex B. Finally, positron emission tomography showed a complete abrogation of hepatic binding of labeled Myrcludex B in <jats:italic toggle="yes">Slc10a1‐/‐ </jats:italic> mice. <jats:italic toggle="yes">Conclusion:</jats:italic> The <jats:italic toggle="yes">Slc10a1</jats:italic>‐knockout mouse model supports the central role of NTCP in hepatic uptake of conjugated BAs and hepatitis B virus preS1/Myrcludex B binding <jats:italic toggle="yes">in vivo</jats:italic>; the NTCP‐independent hepatic BA uptake machinery maintains a (slower) enterohepatic circulation of BAs, although it is occasionally insufficient to clear BAs from the circulation. (H<jats:sc>epatology</jats:sc> 2015;62:207–219)</jats:p>
  • Access State: Open Access