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

Autor: Slijepcevic D; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., Kaufman C; Department of Infectious Diseases and of Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.; Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany., Wichers CG; Department of Molecular Cancer Research, Section of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands., Gilglioni EH; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., Lempp FA; Department of Infectious Diseases and of Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany., Duijst S; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., de Waart DR; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., Elferink RP; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., Mier W; Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany., Stieger B; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland., Beuers U; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands., Urban S; Department of Infectious Diseases and of Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.; German Center for Infection Research, Heidelberg University, Heidelberg, Germany., van de Graaf SF; Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AMC, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2015 Jul; Vol. 62 (1), pp. 207-19. Date of Electronic Publication: 2015 May 08.
DOI: 10.1002/hep.27694
Abstrakt: Unlabelled: The Na(+) -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 Slc10a1-knockout mouse model (Slc10a1 encodes NTCP). Primary Slc10a1(-/-) hepatocytes showed absence of sodium-dependent taurocholic acid uptake, whereas sodium-independent taurocholic acid uptake was unchanged. In vivo, 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 Slc10a1(-/-) mice, explained by increased Asbt and Ostα/β expression. These mice further showed reduced Asbt 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 Slc10a1(-/-) hepatocytes were insensitive to Myrcludex B. Finally, positron emission tomography showed a complete abrogation of hepatic binding of labeled Myrcludex B in Slc10a1(-/-) mice.
Conclusion: The Slc10a1-knockout mouse model supports the central role of NTCP in hepatic uptake of conjugated BAs and hepatitis B virus 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 BAs from the circulation.
(© 2015 by the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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