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Impaired uptake of conjugated bile acids and Hepatitis B Virus preS1-binding in Na+-taurocholate cotransporting polypeptide knockout mice
Davor Slijepcevic1,
Christina Kaufman2,3,
Catharina G.K. Wichers4,
Eduardo H. Gilglioni1,
Florian A. Lempp2,
Suzanne Duijst1,
Dirk R. de Waart1,
Ronald P.J. Oude Elferink1,
Walter Mier3,
Bruno Stieger5,
Ulrich Beuers1,
Stephan Urban2,6 and
Stan F.J. van de Graaf1
DOI: 10.1002/hep.27694
Copyright © 2015 American Association for the Study of Liver Diseases
Issue
Vol. 61 Issue 1
Hepatology
Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)
1 Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology & Hepatology, AMC, Amsterdam, the Netherlands
2 Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Germany
3 Department of Nuclear Medicine, University Hospital Heidelberg, Germany
4 Department of Molecular Cancer Research, Section Metabolic Diseases, University Medical Center Utrecht, the Netherlands
5 Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland
6 German Center for Infection Research, Heidelberg University, Germany
*Correspondence to: Stan van de Graaf, Meibergdreef 69-71, 1105 BK Amsterdam, Phone number: 020-5668832, Fax number: 020-5669190, E-mail address: [email protected]
Publication History
Accepted manuscript online: 10 JAN 2015 04:04AM EST
Manuscript Accepted: 7 JAN 2015
Manuscript Revised: 3 DEC 2014
Manuscript Received: 18 JUL 2014
The Na+-taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane of hepatocytes. NTCP has recently been recognized as the receptor mediating hepatocyte-specific entry of Hepatitis B (HBV) and Hepatitis Delta viruses (HDV). Myrcludex B, a peptidic inhibitor of HBV entry, is assumed to specifically target NTCP. Here, we investigated BA transport and Myrcludex B binding in the first Slc10a1-knockout mouse model (Slc10a1 encodes NTCP). Primary Slc10a1-/- hepatocytes showed absence of sodium-dependent taurocholic acid (TCA) uptake, whereas sodium-independent TCA uptake was unchanged. In vivo, this presented 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 UDCA. Biliary BA output remained intact, while fecal BA excretion was reduced in hypercholanemic Slc10a1-/- mice, explained by increased Asbt and Ostα/β expression. These mice further showed reduced Asbt expression in kidney and increased renal BA excretion. Hepatic uptake of conjugated BAs was potentially affected by downregulation of OATP1A1 and upregulation of OATP1A4. Furthermore, sodium-dependent TCA uptake was inhibited by Myrcludex B in wild-type hepatocytes, while Slc10a1-/- hepatocytes were insensitive to Myrcludex B. Finally, positron emission tomography showed a complete abrogation of hepatic binding of labelled Myrcludex B in Slc10a1-/- mice.
Conclusion: The Slc10a1-knockout mouse model supports the central role of NTCP in hepatic uptake of conjugated BAs and HBV preS1/Myrcludex B binding in vivo. The NTCP-independent hepatic BA uptake machinery maintains a (slower) enterohepatic circulation of BAs, although it is occasionally insufficient to clear the circulation from BAs. This article is protected by copyright. All rights reserved.
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发表于 2015-1-16 19:21