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Review
. 2022 Apr 12:9:879817.
doi: 10.3389/fmolb.2022.879817. eCollection 2022.

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

Yan Li  1 , Jun Zhou  1 , Tianliang Li  1
Affiliations
Review

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

Yan Li et al. Front Mol Biosci. .

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.

Keywords: HBV; HBV entry; NTCP; post-translational regulation; transcriptional regulation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
NTCP transmembrane domains ​in the plasma membrane. The transmembrane protein NTCP has a putative nine transmembrane domains with a topology predicted to consist of an extracellular N-terminus and an intracellular C-terminus.
FIGURE 2
FIGURE 2
Regulation of NTCP expression. Transcriptional and post-translational regulation of NTCP were summarized. (A) Transcriptional regulation, ① Bile acid-induced, FXR-mediated induction of the nuclear repressor SHP is a key mechanism reducing NTCP expression, through its interference with the RXR-RAR heterodimer, HNF-1α and HNF-4α, which have binding sites within the NTCP promoter. FXR expression can be modulated by SIRT1 through HNF-1α; ② STAT5 directly bound to NTCP promoter and mediates NTCP expression; ③ IL-6 down-regulates the expression of NTCP through suppression of HNF1α and HNF4α in JNK pathway-dependent manner, IL-1β down-regulates the expression of NTCP via suppression of the RAR/RXR complex in JNK pathway-dependent manner; ④ Glucocorticoid increases NTCP expression in a GR-dependent manner, which was inhibited by FXR-induced expression of SHP. (B) Post-translational regulation, PP2B and PI3K/PKB/PKC axis facilitate the intracellular movement of NTCP towards the plasma membrane following cAMP activation. Elevated bile acid levels inhibit cAMP activation; (C). NTCP protein abundance was controlled by ubiquitin-proteasome system. Abbreviations: BA, bile acid; FXR, farnesoid X receptor; SHP, small heterodimer partner; HNF-1α, hepatocyte nuclear factor 1 alpha; SIRT1, hepatic sirtuin 1; STAT5, signal transducer and activator of transcription 5; GLE, interferon-gamma (IFN-γ)-activated sequence-like element; GR, glucocorticoid receptor; RXR, retinoid X receptor; RAR, RXR-retinoic acid receptor; PP2B, protein phosphatase 2B; UPS, ubiquitin-proteasome system.
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