Ｃ型肝炎ウイルスによる糖代謝異常の分子機序の解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24590976
• Research Institution: Kobe University
• Principal Investigator: 堀田 博 神戸大学, 医学(系)研究科(研究院), 教授 (40116249)
• Co-Investigator(Kenkyū-buntansha): 勝二 郁夫 神戸大学, 医学(系)研究科(研究院), 准教授 (40356241) ; デン リン 神戸大学, 医学(系)研究科(研究院), 助教 (40437497)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: C型肝炎ウイルス / 感染症 / 糖新生 / Fox01 / MKP3 / アポトーシス / Bim

Outline of Annual Research Achievements

Ｃ型肝炎ウイルス(HCV)は慢性肝炎、肝硬変、肝細胞癌等を引き起こすのみならず、糖・脂質代謝障害と密接な関連があることが知られている。我々は、HCV感染が糖新生制御因子である転写因子FoxO1を脱リン酸化（活性化）状態に維持させること、及び活性化FoxO1により糖新生律速酵素遺伝子群の転写が促進され肝細胞の糖新生が亢進することを明らかにした。また、HCV感染により脱リン酸化酵素MAPK phosphatase-3 (MKP3)のmRNA及びタンパク質発現が亢進すること、MKP3は内在性FoxO1と結合すること、MKP3発現によりFoxO1のSer319リン酸化の程度が低下すること、HCV複製細胞ではMKP3は細胞質に局在することを明らかにした。さらに、FoxO1活性化により高血糖下において細胞のアポトーシスを誘導することが近年明らかにされたアポトーシス誘導因子Bimの発現が、HCV感染による酸化ストレス及びc-Jun N-terminal kinase (JNK)の活性化を通して亢進すること、及び、それに伴ってアポトーシス誘導因子Baxの活性化ならびにcaspase 3の活性化が誘導されアポトーシスが惹起されることを、HCV感染細胞系を用いて実証した。

Research Products

• [Journal Article] A single-amino-acid mutation in hepatitis C virus NS5A disrupts physical and functional interaction with the transcription factor HNF-1α. (2015)
  • Author(s): Matsui C, Sianipar I R, Minami N, Deng L, Hotta H, Shoji I
  • Journal Title: J Gen Virol Volume: in press Pages: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Virocidal activity of Egyptian scorpion venoms against hepatitis C virus. (2015)
  • Author(s): El-Bitar AM, Sarhan MM, Aoki C, Takahara Y, Komoto M, Deng L, Moustafa MA, Hotta H
  • Journal Title: Virol J Volume: 12(1) Pages: 47
  • DOI: 10.1186/s12985-015-0276-6.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The NS5A protein of hepatitis C virus transcriptionally upregulates the AGR3 gene expression. (2015)
  • Author(s): Chen M, Gan X, Deng L, Hotta H
  • Journal Title: Kobe J Med Sci Volume: 61(1) Pages: E27-35
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NS5B induces up-regulation of the BH3-only protein, BIK, essential for the hepatitis C virus RNA replication and viral release. (2015)
  • Author(s): Aweya JJ, Sze CW, Bayega A, Mohd-Ismail NK, Deng L, Hotta H, Tan YJ
  • Journal Title: Virology Volume: 474 Pages: 41-51
  • DOI: 10.1016/j.virol.2014.10.027.
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves. (2014)
  • Author(s): Wahyuni TS, Widyawaruyanti A, Lusida MI, Fuad A, Soetjipto, Fuchino H, Kawahara N, Hayashi Y, Aoki C, Hotta H
  • Journal Title: Fitoterapia Volume: 99 Pages: 276-83
  • DOI: 10.1016/j.fitote.2014.10.011.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of hepatitis C virus heterogeneity on interferon sensitivity: an overview. (2014)
  • Author(s): El-Shamy A, Hotta H
  • Journal Title: World J Gastroenterol. Volume: 20(24) Pages: 7555-69
  • DOI: 10.3748/wjg.v20.i24.7555.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of cell-mediated immune responses in mice by DNA vaccines that express hepatitis C virus NS3 mutants lacking serine protease and NTPase/RNA helicase activities. (2014)
  • Author(s): Ratnoglik SL, Jiang DP, Aoki C, Sudarmono P, Shoji I, Deng L, Hotta H
  • Journal Title: PLoS One Volume: 9(6) Pages: e98877.
  • DOI: 10.1371/journal.pone.0098877.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-28B polymorphisms and response of chronic hepatitis C patients from Indonesia to pegylated interferon/ribavirin treatment. (2014)
  • Author(s): Juniastuti, Wibowo BP, Wibawa ID, Utsumi T, Mustika S, Amin M, Wahyuni RM, Kurniawan H, Hendrayana A, Setiawan PB, Yamani LN, Soetjipto, Yano Y, Hotta H, Hayashi Y, Lusida MI
  • Journal Title: J Clin Microbiol Volume: 52(6) Pages: 2193-5
  • DOI: 10.1128/JCM.00768-14.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Oral administration of genetically modified Bifidobacterium displaying HCV-NS3 multi-epitope fusion protein could induce an HCV-NS3-specific systemic immune response in mice. (2014)
  • Author(s): Takei S, Omoto C, Kitagawa K, Morishita N, Katayama T, Shigemura K, Fujisawa M, Kawabata M, Hotta H, Shirakawa T
  • Journal Title: Vaccine Volume: 32(25) Pages: 3066-74
  • DOI: 10.1016/j.vaccine.2014.03.022.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Aspergillus terreus からの精製物質ロバスタチンはC型肝炎ウイルス感染性粒子放出を促進する (2015)
  • Author(s): 青木千恵, Muhanmad Hanafi, Leonardus B.S. Kardono, 清水洋子, Pratiwi Sudarmono, 堀田博
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Inhibition of hepatitis C virus replication by Chalepin and Pseudane IX isolated from Ruta angustifolia leaves. (2015)
  • Author(s): Wahyuni T S, Widyawaruyanti A, Lusida M I, Fuad A, Soetjipto, Fuchino H, Kawahara N, Hayashi Y, Aoki C, Hotta H
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] C型肝炎ウイルスによるHNF-1α蛋白質の選択的分解機構の解析. (2014)
  • Author(s): 勝二郁夫, 松井千絵子, Imelda Rosalyn Sianipar, 南奈苗, Lin Deng, 堀田博
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Aspergillus terreus 抽出液及びその精製物ロバスタチンは高濃度でC型肝炎ウイルス感染性粒子の放出を促進する. (2014)
  • Author(s): 青木千恵, Muhanmad Hanafi, Leonardus B.S. Kardono, 清水洋子, Pratiwi Sudarmono, 堀田博
  • Organizer: 第67回日本細菌学会関西支部総会学術集会
  • Place of Presentation: 西宮
  • Year and Date: 2014-11-22 – 2014-11-22
• [Presentation] C型肝炎ウイルス感染によるTGF-βスーパーファミリーにおけるSmad2/3とSmad1/5/9経路の脱制御とその分子機序の解明. (2014)
  • Author(s): 松岡陽子, DENG Lin, 朝日朱美, 青木千恵, 勝二郁夫, 堀田博
  • Organizer: 第62回日本ウイルス学会学術集会.
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Ｃ型肝炎ウイルスによるミトコンドリア介在性アポトーシス誘導機構の解明. (2014)
  • Author(s): 甘翔, DENG Lin, 陳明, 勝二郁夫, 堀田博
  • Organizer: 第62回日本ウイルス学会学術集会.
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] C型肝炎ウイルス感染によるHepatocyte nuclear factor (HNF) -1α蛋白質の選択的分解機構 (2014)
  • Author(s): 松井千絵子, 勝二郁夫, Sianipar I R, 南 奈苗, DENG Lin, 堀田博
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] HCV NS5A interacts with lysine methyltransferase SMYD3 and transcriptionally activates the protein disulfide isomerase gene AGR3. (2014)
  • Author(s): Chen M, Gan X, Deng L, Shoji I, Hotta H
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] HCV NS5A protein physically and functionally interacts with an OTU deubiquitinase. (2014)
  • Author(s): Sianipar IR, Shoji I, Matsui C, Minami N, Deng L, Hotta H
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Chalepin and pseudane IX isolated from Ruta angustifolia leaves inhibit hepatitis C virus replication. (2014)
  • Author(s): Wahyuni T S, Widyawaruyanti A, Lusida M I, Fuad A, Soetjipto, Fuchino H, Kawahara N, Hayashi Y, Aoki C, Hotta H
  • Organizer: The 13th Awaji International Forum on Infection and Immunity in Nara.
  • Place of Presentation: Nara, Japan
  • Year and Date: 2014-09-23 – 2014-09-26
• [Presentation] HCV induces Bim/Bax-mediated apoptosis through the ROS/JNK signaling pathway. (2014)
  • Author(s): Deng L, Chen M, Shoji I, Hotta H
  • Organizer: The 21st International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] HCV dysregulates Smad2/3- and Smad1/5-signaling pathways of the TGF-β superfamily. (2014)
  • Author(s): Matsuoka Y, Deng L, Asahi A, Aoki C, Shoji I, Hotta H
  • Organizer: 21st International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] hysical and functional interaction between an OTU deubiquitinase and HCV NS5A protein. (2014)
  • Author(s): Sianipar I R, Shoji I, Matsui C, Minami N, Deng L, Hotta H
  • Organizer: The 21st International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Determinants of specific interaction between hepatitis C virus NS5A and HNF-1α protein. (2014)
  • Author(s): Matsui C, Shoji I, Sianipar I R, Minami N, Deng L, Hotta H
  • Organizer: The 21st International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Remarks] 神戸大学大学院医学研究科微生物学分野 研究内容
  • URL: http://www.med.kobe-u.ac.jp/micro/research-2.htm