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, Jahrgang 8, Nr. 1, 2019, S. 879-894.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -