Regulation of hepatocarcinogenesis by using antagonists to retinoid X receptor alpha RXRalpha.
| Project/Area Number |
15590624
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MORIYA Kyoji The University of Tokyo, Faculty of medicine, Lecturer, 医学部附属病院, 講師 (00272550)
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| 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)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | HCV / Insulin resistance / Lipid metabolism / nuclear receptor / C型肝炎ウイルス / ミトコンドリア |
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| 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
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Report
(3 results)
Research Products
(17 results)
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[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.
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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
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[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
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Journal Title
Infect Control Hosp Epidemiol. 25(7)
Description
「研究成果報告書概要(欧文)」より
Related Report
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[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.
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Journal Title
Infect Control Hosp Epidemiol 25(7)
Pages: 591-594
Related Report
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[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.
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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
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[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.
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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
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