| Project/Area Number |
17390217
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Osaka University |
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Principal Investigator |
TAMURA Shinji Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (30243223)
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| Co-Investigator(Kenkyū-buntansha) |
FUNAHASHI Toru Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (60243234)
KISO Shinichi Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40335352)
WATABE Kenji Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (50379244)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2006: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2005: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | adiponectin / nonalcoholic steatohepatitis / hepatocarcinogenesis / oxidative stress / choline-deficient L-amino acid defined diet / liver fibrosis / lipid peroxide / 8-hydroxydeoxyguanosine / 8-hydroxyguanine / メタボリックシンドローム / LPS / Kuppfer細胞 |
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| Research Abstract |
There is a close relationship obesity and high mortality rate due to cancers, for which obesity and hepatocellular carcinoma (HCC) represent a particularly high risk. Moreover, obesity is an independent risk factor for certain liver diseases such as nonalcoholic steatohepatitis (NASH) which is closely associated with obesity and metabolic syndrome. A proportion of patients with NASH develop cirrhosis and HCC. In the two-hit theory of NASH pathogenesis, the 'first hit' of hepatic steatosis is followed by a 'second hit' including oxidative injuries with an increase in inflammation and progression to fibrosis and HCC.
Adiponectin is expressed exclusively in adipose tissue, and both adiponectin mRNA in adipose tissue and the protein levels in plasma decrease in obesity, which is considered as a key event in pathogenesis of metabolic syndrome. To clarify the molecular mechanism underlying the link between obesity and NASH and its progression to cirrhosis and HCC, we investigated the role of
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adiponectin on development and progression of NASH using adiponectin deficient mice (KO mice). Hepatic steatosis was enhanced to a greater extent in KO mice, compared to wild type (WT) mice after 1-week choline-deficient L-amino acid defined (CDAA) diet. After 24 weeks with CDAA diet, 6 out of 14 KO mice developed liver cirrhosis and hepatic tumors, whereas the all WT mice showed only simple steatosis. In KO mice, markers of oxidative stress (thiobarbituric acid-reactive substances, 8-hydroxydeoxyguanosine-positive cells) were significantly increased compared with WT mice. We also demonstrated that deficiency of adiponectin exacerbated lipopolysaccharide-induced liver injury. Our results indicate that lack of adiponectin enhances the hepatic steatosis, fibrosis, oxidative stress, and inflammation and promotes the hepatic tumor formation in an animal model of NASH.
In conclusions, adiponectin has inhibitory effects on development and progression of NASH and hypoadiponectinemia in obesity could be a risk factor for NASH-related hepatocarcinogenesis. Less
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