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Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation
http://hdl.handle.net/10271/0002000207
http://hdl.handle.net/10271/000200020721700a7c-fd0b-4b28-a396-45ba4c93e798
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
論文本文 (2.7 MB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||||
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| 公開日 | 2024-09-05 | |||||||||||
| タイトル | ||||||||||||
| タイトル | Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation | |||||||||||
| 言語 | en | |||||||||||
| 言語 | ||||||||||||
| 言語 | eng | |||||||||||
| 資源タイプ | ||||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||||
| 資源タイプ | doctoral thesis | |||||||||||
| アクセス権 | ||||||||||||
| アクセス権 | open access | |||||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||||
| その他のタイトル | ||||||||||||
| その他のタイトル | C型肝炎ウイルスによって誘導される鉄蓄積におけるヘプシジンの発現上昇とフェロポーチン1のタンパク質分解切断の役割 | |||||||||||
| 著者 |
太田, 和義
× 太田, 和義
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| 書誌情報 |
en : PLOS Pathogens 巻 19, 号 8, p. e1011591, ページ数 28, 発行日 2023-08-16 |
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| 出版者 | ||||||||||||
| 出版者 | PLOS (Public Library of Science) | |||||||||||
| 言語 | en | |||||||||||
| 権利 | ||||||||||||
| 言語 | en | |||||||||||
| 権利情報 | (C) 2023 Ohta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |||||||||||
| 抄録 | ||||||||||||
| 内容記述タイプ | Abstract | |||||||||||
| 内容記述 | Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells. | |||||||||||
| 言語 | en | |||||||||||
| 抄録 | ||||||||||||
| 内容記述タイプ | Abstract | |||||||||||
| 内容記述 | Author summary Iron plays an important role in many biological processes, including cell proliferation and metabolism, and disruption of iron homeostasis leads to the generation of harmful reactive oxygen species through the Fe2+-triggered Fenton/Haber-Weiss reaction. Iron deposition is often observed in liver tissues of chronic hepatitis C patients, and it has been considered that abnormal iron metabolism is potentially involved in the pathogenesis of HCV. In this study, we show that, in the hepcidin-ferroportin axis, the key mechanism involved in regulation of iron homeostasis, both induction of hepcidin expression and proteolytic cleavage of ferroportin 1 protein induced by HCV infection lead to increased iron levels in the cells, and identify viral factors responsible for the iron accumulation. This is the first study to demonstrate that two mechanisms, transcriptional activation of host cells upon pathogen infection and host protein cleavage by pathogen-derived proteases, work together to result in iron accumulation in host cells. These findings not only deepen our understanding of the mechanisms of HCV-related pathologies, but also lead to the development of new therapies for chronic liver diseases. |
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| 言語 | en | |||||||||||
| 学位名 | ||||||||||||
| 学位名 | 博士（医学） | |||||||||||
| 学位の区分 | ||||||||||||
| 内容記述 | doctoral | |||||||||||
| 学位の分野 | ||||||||||||
| 内容記述 | 医学系研究科 | |||||||||||
| 学位授与機関 | ||||||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||||||
| 学位授与機関識別子 | 13802 | |||||||||||
| 学位授与機関名 | 浜松医科大学 | |||||||||||
| 学位授与年月日 | ||||||||||||
| 学位授与年月日 | 2023-11-17 | |||||||||||
| 学位授与番号 | ||||||||||||
| 学位授与番号 | 甲第960号 | |||||||||||
| ISSN | ||||||||||||
| 収録物識別子タイプ | PISSN | |||||||||||
| 収録物識別子 | 1553-7366 | |||||||||||
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| 収録物識別子タイプ | EISSN | |||||||||||
| 収録物識別子 | 1553-7374 | |||||||||||
| PubMed番号 | ||||||||||||
| 関連タイプ | isIdenticalTo | |||||||||||
| 識別子タイプ | PMID | |||||||||||
| 関連識別子 | 37585449 | |||||||||||
| 出版社DOI | ||||||||||||
| 関連タイプ | isIdenticalTo | |||||||||||
| 識別子タイプ | DOI | |||||||||||
| 関連識別子 | https://doi.org/10.1371/journal.ppat.1011591 | |||||||||||
| 著者版フラグ | ||||||||||||
| 出版タイプ | VoR | |||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||
