Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection
ABSTRACTHepatocyte 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2019.1625728 |
| _version_ | 1827579261766074368 |
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| author | Ying Yan Lena Allweiss Danli Yang Jingting Kang Jianwen Wang Xiangjun Qian Ting Zhang Hui Liu Lu Wang Shuhong Liu Jianhua Sui Xiangmei Chen Maura Dandri Jingmin Zhao Fengmin Lu |
| author_facet | Ying Yan Lena Allweiss Danli Yang Jingting Kang Jianwen Wang Xiangjun Qian Ting Zhang Hui Liu Lu Wang Shuhong Liu Jianhua Sui Xiangmei Chen Maura Dandri Jingmin Zhao Fengmin Lu |
| author_sort | Ying Yan |
| collection | DOAJ |
| description | ABSTRACTHepatocyte 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. |
| first_indexed | 2024-03-08T21:59:08Z |
| format | Article |
| id | doaj.art-8ecaf7f5b5af477780b48d34e54969f1 |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-08T21:59:08Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-8ecaf7f5b5af477780b48d34e54969f12023-12-19T16:09:57ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512019-01-018187989410.1080/22221751.2019.1625728Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infectionYing Yan0Lena Allweiss1Danli Yang2Jingting Kang3Jianwen Wang4Xiangjun Qian5Ting Zhang6Hui Liu7Lu Wang8Shuhong Liu9Jianhua Sui10Xiangmei Chen11Maura Dandri12Jingmin Zhao13Fengmin Lu14State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaDepartment of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaDepartment of Pathology and Hepatology, The 5th Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaBiologics Research Center, National Institute of Biological Sciences, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaDepartment of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Pathology and Hepatology, The 5th Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaState Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of ChinaABSTRACTHepatocyte 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.https://www.tandfonline.com/doi/10.1080/22221751.2019.1625728Sodium taurocholate cotransporting polypeptide (NTCP)hepatocyte proliferationhepatitis B virus (HBV) infectionchronic hepatitis B (CHB)antiviral therapyp53 |
| spellingShingle | Ying Yan Lena Allweiss Danli Yang Jingting Kang Jianwen Wang Xiangjun Qian Ting Zhang Hui Liu Lu Wang Shuhong Liu Jianhua Sui Xiangmei Chen Maura Dandri Jingmin Zhao Fengmin Lu Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection Emerging Microbes and Infections Sodium taurocholate cotransporting polypeptide (NTCP) hepatocyte proliferation hepatitis B virus (HBV) infection chronic hepatitis B (CHB) antiviral therapy p53 |
| title | Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection |
| title_full | Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection |
| title_fullStr | Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection |
| title_full_unstemmed | Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection |
| title_short | Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection |
| title_sort | down regulation of cell membrane localized ntcp expression in proliferating hepatocytes prevents hepatitis b virus infection |
| topic | Sodium taurocholate cotransporting polypeptide (NTCP) hepatocyte proliferation hepatitis B virus (HBV) infection chronic hepatitis B (CHB) antiviral therapy p53 |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2019.1625728 |
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