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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection

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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection. / Yan, Ying; Allweiss, Lena; Yang, Danli; Kang, Jingting; Wang, Jianwen; Qian, Xiangjun; Zhang, Ting; Liu, Hui; Wang, Lu; Liu, Shuhong; Sui, Jianhua; Chen, Xiangmei; Dandri, Maura; Zhao, Jingmin; Lu, Fengmin.

In: EMERG MICROBES INFEC, Vol. 8, No. 1, 2019, p. 879-894.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Yan, Y, Allweiss, L, Yang, D, Kang, J, Wang, J, Qian, X, Zhang, T, Liu, H, Wang, L, Liu, S, Sui, J, Chen, X, Dandri, M, Zhao, J & Lu, F 2019, 'Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection', EMERG MICROBES INFEC, vol. 8, no. 1, pp. 879-894. https://doi.org/10.1080/22221751.2019.1625728

APA

Yan, Y., Allweiss, L., Yang, D., Kang, J., Wang, J., Qian, X., Zhang, T., Liu, H., Wang, L., Liu, S., Sui, J., Chen, X., Dandri, M., Zhao, J., & Lu, F. (2019). Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection. EMERG MICROBES INFEC, 8(1), 879-894. https://doi.org/10.1080/22221751.2019.1625728

Vancouver

Yan Y, Allweiss L, Yang D, Kang J, Wang J, Qian X et al. Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection. EMERG MICROBES INFEC. 2019;8(1):879-894. https://doi.org/10.1080/22221751.2019.1625728

Bibtex

@article{ff33cf102c8444168b0963aa073558ed,
title = "Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection",
abstract = "Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells and in liver-humanized mice. In patients, lower NTCP protein expression was correlated well with higher levels of hepatocyte proliferation and less HBsAg expression in HBV-related focal nodular hyperplasia (FNH) tissues. Clinically, significantly lower NTCP protein expression was correlated with more active hepatocyte proliferation in CHB patients with severe active necroinflammation and better antiviral treatment outcome. Mechanistically, the activation of cell cycle regulatory genes p53, S-phase kinase-associated protein 2 (SKP2) and cyclin D1 during cell proliferation, as well as proliferative and inflammatory cytokine Interleukin-6 (IL-6) could transcriptionally down-regulate NTCP expression. From these aspects, we conclude that within the milieu of hepatocyte proliferation, down-regulation of cell membrane localized NTCP expression level renders nascent hepatocytes resistant to HBV reinfection. This may accelerate virus clearance during immune-mediated cell death and compensatory proliferation of survival hepatocytes.",
keywords = "Animals, Cell Membrane/genetics, Cell Proliferation, Down-Regulation, Female, Hep G2 Cells, Hepatitis B/genetics, Hepatitis B virus/genetics, Hepatocytes/cytology, Humans, Male, Mice, Mice, Inbred C57BL, Organic Anion Transporters, Sodium-Dependent/genetics, Receptors, Virus/genetics, Symporters/genetics",
author = "Ying Yan and Lena Allweiss and Danli Yang and Jingting Kang and Jianwen Wang and Xiangjun Qian and Ting Zhang and Hui Liu and Lu Wang and Shuhong Liu and Jianhua Sui and Xiangmei Chen and Maura Dandri and Jingmin Zhao and Fengmin Lu",
year = "2019",
doi = "10.1080/22221751.2019.1625728",
language = "English",
volume = "8",
pages = "879--894",
journal = "EMERG MICROBES INFEC",
issn = "2222-1751",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection

AU - Yan, Ying

AU - Allweiss, Lena

AU - Yang, Danli

AU - Kang, Jingting

AU - Wang, Jianwen

AU - Qian, Xiangjun

AU - Zhang, Ting

AU - Liu, Hui

AU - Wang, Lu

AU - Liu, Shuhong

AU - Sui, Jianhua

AU - Chen, Xiangmei

AU - Dandri, Maura

AU - Zhao, Jingmin

AU - Lu, Fengmin

PY - 2019

Y1 - 2019

N2 - Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells and in liver-humanized mice. In patients, lower NTCP protein expression was correlated well with higher levels of hepatocyte proliferation and less HBsAg expression in HBV-related focal nodular hyperplasia (FNH) tissues. Clinically, significantly lower NTCP protein expression was correlated with more active hepatocyte proliferation in CHB patients with severe active necroinflammation and better antiviral treatment outcome. Mechanistically, the activation of cell cycle regulatory genes p53, S-phase kinase-associated protein 2 (SKP2) and cyclin D1 during cell proliferation, as well as proliferative and inflammatory cytokine Interleukin-6 (IL-6) could transcriptionally down-regulate NTCP expression. From these aspects, we conclude that within the milieu of hepatocyte proliferation, down-regulation of cell membrane localized NTCP expression level renders nascent hepatocytes resistant to HBV reinfection. This may accelerate virus clearance during immune-mediated cell death and compensatory proliferation of survival hepatocytes.

AB - Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells and in liver-humanized mice. In patients, lower NTCP protein expression was correlated well with higher levels of hepatocyte proliferation and less HBsAg expression in HBV-related focal nodular hyperplasia (FNH) tissues. Clinically, significantly lower NTCP protein expression was correlated with more active hepatocyte proliferation in CHB patients with severe active necroinflammation and better antiviral treatment outcome. Mechanistically, the activation of cell cycle regulatory genes p53, S-phase kinase-associated protein 2 (SKP2) and cyclin D1 during cell proliferation, as well as proliferative and inflammatory cytokine Interleukin-6 (IL-6) could transcriptionally down-regulate NTCP expression. From these aspects, we conclude that within the milieu of hepatocyte proliferation, down-regulation of cell membrane localized NTCP expression level renders nascent hepatocytes resistant to HBV reinfection. This may accelerate virus clearance during immune-mediated cell death and compensatory proliferation of survival hepatocytes.

KW - Animals

KW - Cell Membrane/genetics

KW - Cell Proliferation

KW - Down-Regulation

KW - Female

KW - Hep G2 Cells

KW - Hepatitis B/genetics

KW - Hepatitis B virus/genetics

KW - Hepatocytes/cytology

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Organic Anion Transporters, Sodium-Dependent/genetics

KW - Receptors, Virus/genetics

KW - Symporters/genetics

U2 - 10.1080/22221751.2019.1625728

DO - 10.1080/22221751.2019.1625728

M3 - SCORING: Journal article

C2 - 31179847

VL - 8

SP - 879

EP - 894

JO - EMERG MICROBES INFEC

JF - EMERG MICROBES INFEC

SN - 2222-1751

IS - 1

ER -