2013 Fiscal Year Research-status Report
非アルコール性脂肪性肝炎の病態形成におけるサイトグロビンの関与
| Project/Area Number |
25860554
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Research Institution | Osaka City University |
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Principal Investigator |
LE THUY 大阪市立大学, 医学(系)研究科(研究院), 研究員 (10572175)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Keywords | CYGB / HSCS / NASH / LIVER FIBROSIS / LIVER CANCER / OXIDATIVE STRESS |
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| Research Abstract |
NASH model was made by feeding Cygb-null (Cygb-/-) and wild-type (WT) mice with choline-deficient amino acid-defined (CDAA) or choline-supplied amino acid-defined (CSAA) diet for 8, 16, and 32 weeks. Cygb-/- mice responded to CDAA diet stress with significantly exacerbation in steatohepatitis and fibrosis at any time points compared to WT mice. Surprisingly, at 32 weeks, unlike no tumor formation in WT mice, 100% of Cygb-/- mice developed liver cancer along with activated ERK and AKT signalings. Primary HSCs isolated from Cygb-/- mice (HSCsCygb-null) reveals “priming condition” as indicated by the augmented expression of O2- production, fibrosis-related genes including αSma, collagen 1a1, and Tgfβ1, and some cytokines and chemokine ligands compared to HSCsCygb-wild. HSCsCygb-wild transfected with Cygb siRNA exhibited the same phenotype of HSCCygb-null. Moreover, HSCCygb-null showed increase in expression of chemokines when co-cultured with Hepa 1-6 cells. Importantly, altered expression of 31 genes involved in the metabolism of reactive oxygen species including myeloperoxidase was identified in Cygb-/- mice. Either treatment with N-acetylcysteine or macrophage deletion in CDAA-fed Cygb-/- mice eliminated the fibro-inflammatory and oxidative reaction in vivo.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
I have finished my first plan on performing NASH model using Cygb KO mice. The results seem very interesting, in which Cygb KO mice showed strong sensitive to diet induced liver tumour formation. We also found the dominant of oxidative stress induction in Cygb KO mice. We are writing the manuscript for submission.
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| Strategy for Future Research Activity |
Now, we are concerning to the second plan, in which primary HSCs are isolated from the WT and Cygb KO mice, then they will be culture in single or in co-culture with mouse hepatoma cell lines to assess the interaction between them, and to examine the effect of Cygb on the development of cancer cells. LX-2, the common human HSCs also used for co-culture with human hepatoma cell line-HEPG2/Huh7 to find out the mechanism action of Cygb in vitro.
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[Journal Article] Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver2014
Author(s)
Hiroyuki Motoyama, Tohru Komiya, Le Thi Thanh Thuy, Akihiro Tamori, Masaru Enomoto, Hiroyasu Morikawa, Shuji Iwai, Sawako Uchida-Kobayashi, Hideki Fujii, Atsushi Hagihara, Etsushi Kawamura, Yoshiki Murakami, Katsutoshi Yoshizato, and Norifumi Kawada
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Journal Title
Laboratory Investigation
Volume: 94
Pages: 194-207
DOI
Peer Reviewed
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