The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses

Abstract

Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research.

Keywords: Anti-viral therapy; Bile acid transport; Hepatocytes; Host factor; Liver cell biology.

Fig. 1

Model of the functional role of NTCP in hepatic bile acid transport and metabolism. Transport of bile acids from portal blood into hepatocytes via NTCP depends on a sodium gradient and is inhibited by CsA or ezetimibe. Secretion into the bile canaliculus via bile salt export pump (BSEP) in an ATP-dependent manner and synthesis from cholesterol are regulated by bile acid-mediated activation of FXR. cAMP mediates dephosphorylation and membrane translocation of NTCP. NTCP sodium taurocholate co-transporting polypeptide, BSEP bile salt export pump, FXR Farnesoid X Receptor, SHP small heterodimer partner, CYP7A1 cholesterol 7α-hydroxylase, BA bile acid, TJ tight junction, CsA cyclosporin A, cAMP cyclic adenosine monophosphate

Fig. 2

Model of interactions between NTCP and the entry of HBV, HDV, and HCV in hepatocytes. After initial attachment to HSPG including GPC5, HBV and HDV virions bind to the receptor NTCP through the preS1-domain of the large envelope protein. NTCP inhibitors CsA and ezetimibe block viral entry like preS1-derived MyrB and CsA-derived SCY995. NTCP modulates HCV infection by interfering with innate immune responses. Bile acids interfere with the IFN signaling pathway and thereby favor HCV entry. Inhibition of NTCP-mediated bile acid import into hepatocytes promotes inhibition of HCV entry through the upregulation of ISGs including IFITMs. HBV hepatitis B virus, HCV hepatitis C virus, HDV hepatitis D virus, HSPG heparan sulfate proteoglycan, GPC5 glypican-5, NTCP sodium taurocholate co-transporting polypeptide, MyrB myrcludex B, CsA cyclosporin A, SCY995 synthesized CsA derivative 995, IFN interferon, IFNAR IFN-α/β receptor, JAK Janus kinase, STAT signal transducer and activator of transcription, IRF9 Interferon regulatory factor 9, ISRE IFN-sensitive response element, ISG IFN-stimulated gene, IFITM IFN-induced transmembrane protein, CLDN1 Claudin 1, CD81 cluster of differentiation 81, BA bile acid, TJ tight junction