Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes

JOURNAL OF HEPATOLOGY

卷:61

Article

Koenig, Alexander^1,3  Doering, Barbara²  Mohr, Christina^1,3  Geipel, Andreas^1,3  Geyer, Joachim²  Glebe, Dieter^1,3 

[1] Univ Giessen, Natl Reference Ctr Hepatitis B&D Viruses, Biomed Res Ctr Seltersberg, Inst Med Virol, D-35392 Giessen, Germany

[2] Univ Giessen, Inst Pharmacol & Toxicol, Biomed Res Ctr Seltersberg, D-35392 Giessen, Germany

[3] German Ctr Infect Res DZIF, Tubingen, Germany

关键词: Hepatitis B virus;    Receptor;    Infection;    NTCP;    ASBT;    SOAT;    Therapy;    Bile acids;    Ezetimibe;    Transport;   

DOI  :  10.1016/j.jhep.2014.05.018

来源: Elsevier

【 摘 要 】

Background & Aims: The human liver bile acid transporter Na+/taurocholate cotransporting polypeptide (NTCP) has recently been identified as liver-specific receptor for infection of hepatitis B virus (HBV), which attaches via the myristoylated preS1 (myr-preS1) peptide domain of its large surface protein to NTCP. Since binding of the myr-preS1 peptide to NTCP is an initiating step of HBV infection, we investigated if this process interferes with the physiological bile acid transport function of NTCP. Methods: HBV infection, myr-preS1 peptide binding, and bile acid transport assays were performed with primary Tupaia belangeri (PTH) and human (PHH) hepatocytes as well as NTCP-transfected human hepatoma HepG2 cells allowing regulated NTCP expression, in the presence of various bile acids, ezetimibe, and myr-preS1 peptides. Results: The myr-preS1 peptide of HBV inhibited bile acid transport in PTH and PHH as well as in NTCP-expressing HEK293 and HepG2 cells. Inversely, HBV infection of PTH, PHH, and NTCP-transfected HepG2 cells was inhibited in a concentration-dependent manner by taurine and glycine conjugates of cholic acid and ursodeoxycholic acid as well as by ezetimibe. In NTCP-HepG2 cells and PTH, NTCP expression, NTCP transport function, myr-preS1 peptide binding, and HBV infection followed comparable kinetics. Conclusions: Myr-preS1 virus binding to NTCP, necessary for productive HBV infection, interferes with the physiological bile acid transport function of NTCP. Therefore, HBV infection via NTCP may be lockable by NTCP substrates and NTCP-inhibiting drugs. This opens a completely new way for an efficient management of HBV infection by the use of NTCP-directed drugs. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free