• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Regulation of hepatocarcinogenesis by using antagonists to retinoid X receptor alpha RXRalpha.

Research Project

Project/Area Number 15590624
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

MORIYA Kyoji  The University of Tokyo, Faculty of medicine, Lecturer, 医学部附属病院, 講師 (00272550)

Co-Investigator(Kenkyū-buntansha) SHINTANI Yoshizumi  The University of Tokyo, Faculty of medicine, Assistant, 医学部附属病院, 助手 (80261965)
FUJIE Hajime  The University of Tokyo, Faculty of medicine, Assistant, 医学部附属病院, 助手 (90332577)
MIYOSHI Hideyuki  The University of Tokyo, Faculty of medicine, Medical Staff, 医学部附属病院, 医員
TSUTSUMI Takeya  The University of Tokyo, Faculty of medicine, Medical Staff, 医学部附属病院, 医員
KOIKE Kazuhiko  The University of Tokyo, Faculty of medicine, Professor, 医学部附属病院, 教授 (80240703)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsHCV / Insulin resistance / Lipid metabolism / nuclear receptor / C型肝炎ウイルス / ミトコンドリア
Research Abstract

1)A mouse model transgenic for the HCV core gene exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. Administration of an anti-tumor necrosis factor-alpha antibody restored insulin sensitivity. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.
2)A case control study of serum apolipoproteins revealed that not only apolipoprotein B but also apolipoprotein CII and apolipoprotein CIII levels were significantly reduced, while apolipoprotein AI, AII and E levels were similar in patients infected with genotype 1b HCV and those with HBV or genotype 2a HCV.
3)We report the direct interaction of HCV core protein with retinoid X receptor alpha … More (RXRalpha). The core protein binds to the DNA-binding domain of RXRalpha, leading to increase the DNA binding of RXRalpha to its responsive element. Using promoter genes we also show that the expression of the core protein enhances the transcriptional activity regulated by the RXRalpha homodimer as well as by the heterodimer with peroxisome proliferator activated receptor alpha. Now administration of antagonists and agonists of RXRalpha is studied.
4)We examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased.
5)We have identified proteasome activator PA28gamma (11S regulator gamma) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. Deletion of the PA28gamma-binding region from the HCV core protein or knockout of the PA28gamma gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28gamma enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28gamma-dependent pathway through which HCV pathogenesis may be exerted.
6)Methylation-specific PCR was performed for the analysis of methylation status both in the 5'-noncoding region and the CpG island of SOCS-1 from 22 HCC tissue samples with adjacent non-HCC tissue samples and from two cell lines. This study showed that aberrant methylation of the SOCS-1 had a significant correlation with HCC. The rate of aberrant methylation was similar in the 5'-noncoding region and in the CpG island. Aberrant methylation of the SOCS-1 may be associated with hepatocellular carcinoma. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (17 results)

All 2004 2003 Other

All Journal Article (15 results) Publications (2 results)

  • [Journal Article] Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma.2004

    • Author(s)
      Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi T, Makuuchi M, Kimura S, Koike K.
    • Journal Title

      Journal of Gastroenterology 39(6)

      Pages: 563-569

    • NAID

      10013296326

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus infection and diabetes : direct involvement of the virus in the development of insulin resistance.2004

    • Author(s)
      Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K.
    • Journal Title

      Gastroenterology 126(3)

      Pages: 840-848

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan2004

    • Author(s)
      Hatakeyama S, Moriya K, Itoyama S, Nukui Y, Uchida M, Shintani Y, Morisawa Y, Kimura S.
    • Journal Title

      Infection Control and Hospital Epidemiology 25(7)

      Pages: 591-594

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma.2004

    • Author(s)
      Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi T, Makuuchi M, Kimura S, Koike K.
    • Journal Title

      J Gastroenterol. 39(6)

      Pages: 563-569

    • NAID

      10013296326

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus infection and diabetes : direct involvement of the virus in the development of insulin resistance.2004

    • Author(s)
      Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K.
    • Journal Title

      Gastraenterolagy. 126(3)

      Pages: 840-848

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan. International meeting2004

    • Author(s)
      Hatakeyama S, Moriya K, Itoyama S, Nukui Y, Uchida M, Shintani Y, Morisawa Y, Kimura S
    • Journal Title

      Infect Control Hosp Epidemiol. 25(7)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Methylation status of suppressor of cytokine sigasling-1 gene in hepatocellular carcinoma2004

    • Author(s)
      Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi T, Makuuchi M, Kimura S, Koike K.
    • Journal Title

      J Gastroenterol 39(6)

      Pages: 563-569

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hepatitis C virus infection and diabetes : direct involvement of the virus in the develonment of insulin resistance2004

    • Author(s)
      Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K.
    • Journal Title

      Gastroenterology 126(3)

      Pages: 840-848

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan2004

    • Author(s)
      Hatakeyama S, Moriya K, Itoyama S, Nukui Y, Uchida M, Shintani Y, Morisawa Y, Kimura S.
    • Journal Title

      Infect Control Hosp Epidemiol 25(7)

      Pages: 591-594

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.2003

    • Author(s)
      Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, Matsuura Y, Koike K, Miyamura T.
    • Journal Title

      Hepatology 38(4)

      Pages: 820-828

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein.2003

    • Author(s)
      Moriishi K, Okabayashi T, Nakai K, Moriya K, Koike K, Murata S, Chiba T, Tanaka K, Suzuki R, Suzuki T, Miyamura T, Matsuura Y.
    • Journal Title

      Journal of Virology 77(19)

      Pages: 10237-10249

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Serum lipid profile of patients with genotype 1b hepatitis C viral infection in Japan2003

    • Author(s)
      Moriya K, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Yotsuyanagi H, Iino S, Kimura S, Koike K.
    • Journal Title

      Hepatology Research 25(4)

      Pages: 371-376

    • NAID

      50000829733

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.2003

    • Author(s)
      Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, Matsuura Y, Koike K, Miyamura T.
    • Journal Title

      Hepatology. 88(4)

      Pages: 820-828

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein.2003

    • Author(s)
      Moriishi K, Okabayashi T, Nakai K, Moriya K, Koike K, Murata S, Chiba T, Tanaka K, Suzuki R, Suzuki T, Miyamura T, Matsuura Y.
    • Journal Title

      J Virol. 77(19)

      Pages: 10237-10249

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Serum lipid profile of patients with genotype 1b hepatitis C viral infection in Japan.2003

    • Author(s)
      Moriya K, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Yotsuyanagi H, Iino S, Kimura S, Koike K.
    • Journal Title

      Hepatol Res. 25(4)

      Pages: 371-376

    • NAID

      50000829733

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Shintani Y, Moriya K, et al.: "Hepatitis C virus infection and diabetes : Direct involvement of the virus in the development of insulin resistance."Gastroenterology. 126・3. 840-848 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Moriya K, Shintani Y, et al.: "Serum lipid profile of patients with genotype 1b hepatitis C viral infection in Japan."Hepatol Res.. 25・4. 371-376 (2003)

    • Related Report
      2003 Annual Research Report

URL: 

Published: 2003-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi