在肝细胞中的胆汁酸转运蛋白和乙肝病毒受体的Na +/牛磺胆cot

StephenW

Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes
Alexander König†,Barbara Döring†,Christina Mohr,Andreas Geipel,Joachim Geyer‡ ,Dieter Glebe‡email
†These authors contributed equally to the work.
‡These authors share senior authorship.
Received: October 31, 2013; Received in revised form: May 6, 2014; Accepted: May 7, 2014; Published Online: May 15, 2014
DOI: http://dx.doi.org/10.1016/j.jhep.2014.05.018

   
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.

StephenW

在肝细胞中的胆汁酸转运蛋白和乙肝病毒受体的Na +/牛磺胆cotransporting多肽（NTCP）的动力学
亚历山大·柯尼希†，芭芭拉DÖRING†，克里斯蒂娜莫尔，安德烈亚斯·盖佩尔，约阿希姆格耶‡迪特尔·格里布‡电子邮件
†这些同等贡献的工作。
‡这些作者分享资深作者。
投稿时间：2013年10月31日;收到修改稿：2014年5月6日;接受日期：2014年5月7日;发表时间：2014年5月15日
DOI：http://dx.doi.org/10.1016/j.jhep.2014.05.018

   
背景与目的

人类肝脏胆汁酸转运体的Na +/牛磺胆cotransporting多肽（NTCP）最近被鉴定为肝特异性受体对乙型肝炎病毒（HBV），通过肉豆蔻酰化前S1（MYR-前S1）的肽，其大的表面区，其高度的感染蛋白NTCP。由于马币前S1肽NTCP结合是HBV感染的起始阶段，我们调查，如果这个过程中干扰NTCP的生理胆汁酸转运功能。
方法

HBV感染，马币前S1肽结合，与胆汁酸转运测定法与主树鼩（PTH）和人（PHH）的肝细胞以及NTCP转染人肝癌细胞株HepG2细胞，允许稳压NTCP表达表现，在各种胆汁的存在酸，依替米贝，和马币前S1肽。
结果

该MYR-前S1肽在PTH和PHH以及在NTCP表达的HEK293和HepG2细胞中的HBV抑制胆汁酸的交通工具。相反地​​，HBV感染的PTH，PHH和NTCP转染的HepG2细胞的抑制在由胆酸和熊去氧胆酸的牛磺酸和甘氨酸偶联物以浓度依赖的方式，以及由依泽替米贝。在NTCP-HepG2细胞和PTH，NTCP表达NTCP转运功能，马币前S1肽结合，与HBV感染遵循类似的动力学。
结论

马币前S1病毒结合NTCP，必要的生产性HBV感染，干扰了NTCP的生理胆汁酸转运功能。因此，HBV感染通过NTCP可上锁的NTCP由基材和NTCP抑制药物。这将打开HBV感染通过使用NTCP导向药物的有效管理一种全新的方式。