Regulation of the HBV Entry Receptor NTCP and its Potential in Hepatitis B Treatment

Abstract

Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for more than 250 million cases of chronic liver infection, a condition that can lead to liver inflammation, cirrhosis, and hepatocellular carcinoma. Sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes and a mediator of bile acid transport, has been identified as the receptor responsible for the cellular entry of both HBV and its satellite, hepatitis delta virus (HDV). This has led to significant advances in our understanding of the HBV life cycle, especially the early steps of infection. HepG2-NTCP cells and human NTCP-expressing transgenic mice have been employed as the primary cell culture and animal models, respectively, for the study of HBV, and represent valuable approaches for investigating its basic biology and developing treatments for infection. However, the mechanisms involved in the regulation of NTCP transcription, translation, post-translational modification, and transport are still largely elusive. Improvements in our understanding of NTCP biology would likely facilitate the design of new therapeutic drugs for the prevention of the de novo infection of naïve hepatocytes. In this review, we provide critical findings regarding NTCP biology and discuss important questions that remain unanswered.

Characterization of mutations in Hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021-2022

“…The HBV receptor is located at amino acids 2-48 counting from the N-terminus of the large-envelope protein preS1 [45][46][47][48], of which amino acids 9-18 are essential for HBV receptor function [26].…”

HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis

“…HBV entry into the cell is mediated by a low-specificity binding between hepatitis B surface antigen (HBsAg) and heparan sulfate proteoglycans (HSPGs) present on the surface of the hepatocyte (Figure 1) [10]. This low-affinity binding creates the conditions for a high-affinity interaction between a specific domain of HBV envelope and the sodium taurocholate co-transporting polypeptide (NTCP), which serves as a functional receptor for HBV [11]. NTCP is a bile salt transporter located predominantly on the hepatocyte basolateral membrane.…”

“…Probably, the same co-transporter has a main role also in the interaction with hepatitis D virus (HDV) [12]. These interactions are followed by the endocytosis of the virion, which This low-affinity binding creates the conditions for a high-affinity interaction between a specific domain of HBV envelope and the sodium taurocholate co-transporting polypeptide (NTCP), which serves as a functional receptor for HBV [11]. NTCP is a bile salt transporter located predominantly on the hepatocyte basolateral membrane.…”

Forthcoming Developments in Models to Study the Hepatitis B Virus Replication Cycle, Pathogenesis, and Pharmacological Advancements

“…NTCP is a functional receptor molecule for the HBV virus and is located on the sinusoidal/basolateral side of the parenchymal cells of the hepatocytes. 154 It is a membrane-localized protein synthesized in the liver, and its principal role is characterized by its peculiar expression. 155 In liver cells, NTCP serves as a transporter.…”