Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes.
OBJECTIVE
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.
Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany; German Center for Infection Research (DZIF), Germany.
Alexander
A
König
Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany.
Barbara
B
Döring
Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany; German Center for Infection Research (DZIF), Germany.
Christina
C
Mohr
Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany; German Center for Infection Research (DZIF), Germany.
Andreas
A
Geipel
Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany.
Joachim
J
Geyer
Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany; German Center for Infection Research (DZIF), Germany. Electronic address: dieter.glebe@viro.med.uni-giessen.de.
Dieter
D
Glebe
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000378:metabolism / Q000821:virology; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D014417:Tupaia; D014764:Viral Proteins / Q000378:metabolism; D053586:Virus Internalization
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D014764:Viral Proteins; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter
ASBT; Bile acids; Ezetimibe; Hepatitis B virus; Infection; NTCP; Receptor; SOAT; Therapy; Transport