| Project/Area Number |
18590736
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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 | Yamaguchi University |
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Principal Investigator |
HINO Keisuke Yamaguchi University, Graduate Scliool of Medicine, Professor (80228741)
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| Co-Investigator(Kenkyū-buntansha) |
KORENAGA Masaaki Yamaguchi Univesity, Hospital, Assistant professor (70420536)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,920,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | hepatitis C / henatocellular carcinoma / oxidative stress / iron metabolism / reactive Oxygen species / transgenic mice / hepcidin / CCAT / enhancer-binding protein / hepcidin / CCAAT enhancer binding protein / CHOP / C型肝炎ウイルス |
|---|
| Research Abstract |
Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis and how hepatic iron overload develops. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma and to clarify the mechanisms by which hepatic iron overload develops. Relationship between hepatic iron overload and hepatocarcinogenesis: Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in three other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguan
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osine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet, but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet, but not in mice in other groups at 12 months after initiation of feeding. Mechanisms by which hepatic iron overload develops: Transgenic mice had increased hepatic and serum iron concentrations, decreased splenic iron concentration and lower hepcidin expression in the liver accompanied by higher expression of ferroportin in the duodenum, spleen and liver. Transgenic mice showed no inflammation in the liver, but preserved the ability to induce hepcidin in response to proinflammatory cytokines induced by lipopolysaccharide. Hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein alpha (C/EBPα) were down-regulated concomitant with increased expression of C/EBPα homology protein (CHOP), an inhibitor of C/EBP DNA binding activity, and with increased levels of reactive oxygen species (ROS) in transgenic mice at the ages of 8 and 14 months. Less
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