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Iron metabolic disorder and hepatocarcinogenesis in hepatitis C

丙型肝炎铁代谢紊乱与肝癌发生

基本信息

批准号：
18590736
负责人：
HINO Keisuke
金额：
$ 2.51万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590736/
关键词：
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

项目摘要

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 … More 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

尽管有证据表明慢性丙型肝炎患者存在肝脏铁超载，但铁超载是否与肝癌发生有关以及肝脏铁超载如何发展仍不清楚。本研究的目的是确定铁超载是否有助于肝细胞癌的发展，并阐明肝铁超载发展的机制。肝脏铁超负荷与肝癌发生的关系：喂食过量铁饮食的小鼠肝脏铁浓度与慢性丙型肝炎患者的肝脏铁浓度相当。在转基因和非转基因肝脏中没有炎症。与其他三组小鼠相比，喂养过量铁饮食的转基因小鼠在6个月时表现出明显的肝脏脂肪变性，包括小叶中心微泡型，线粒体超微结构改变和脂肪酸降解活性降低，以及肝脏脂质过氧化产物和8-羟基-2 ′-脱氧鸟苷含量增加 ...更多信息在开始喂养后12个月时，增殖的肝细胞的数量显着增加，喂养过量铁饮食的小鼠，但转基因和非转基因小鼠之间没有差异。包括HCC在内的肝肿瘤在11只（45%）喂食过量铁饮食的转基因小鼠中有5只（45%）发生，但在开始喂食后12个月，其他组小鼠中没有发生。肝脏铁过载发展的机制：转基因小鼠肝脏和血清铁浓度增加，脾脏铁浓度降低，肝脏中铁调素表达降低，同时十二指肠、脾脏和肝脏中膜铁转运蛋白表达升高。转基因小鼠的肝脏没有炎症，但保留了诱导hepcidin的能力，以响应脂多糖诱导的促炎细胞因子。在8月龄和14月龄的转基因小鼠中，铁调素启动子活性和CCAAT/增强子结合蛋白α（C/EBPα）的DNA结合活性下调，同时C/EBPα同源蛋白（CHOP）（C/EBP α DNA结合活性抑制剂）的表达增加，活性氧（ROS）水平增加。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stronger Neo‐Minophagen C™, a glycyrrhizin‐containing preparation, protects liver against carbon tetrachloride‐induced oxidative stress in transgenic mice expressing the hepatitis C virus polyprotein

DOI：
10.1111/j.1478-3231.2007.01492.x
发表时间：
2007-08
期刊：
Liver International
影响因子：
6.7
作者：
I. Hidaka;K. Hino;M. Korenaga;T. Gondo;S. Nishina;Miye Ando;M. Okuda;I. Sakaida
通讯作者：
I. Hidaka;K. Hino;M. Korenaga;T. Gondo;S. Nishina;Miye Ando;M. Okuda;I. Sakaida

Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species