Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription
Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription
复制标题
DOI：
10.1053/j.gastro.2007.10.011
复制
发表时间：
2008-01-01
期刊：
影响因子：
29.4
通讯作者：
Sakaida, Isao
中科院分区：
文献类型：
--
作者：
Nishina, Sohji;Hino, Keisuke;Sakaida, Isao
背景和目标：尽管有大量的临床证据，但丙型肝炎病毒（HCV）相关慢性肝病患者肝脏铁超载的机制仍不清楚。本研究的目的是调查如何在HCV蛋白存在下肝脏铁超载的发展。研究方法：表达HCV多聚蛋白的雄性转基因小鼠和非转基因对照小鼠（C57 BL/6）进行了体内和体外铁浓度的评估，在肝脏，脾脏，血清和铁调节分子。结果如下：转基因小鼠肝脏和血清铁浓度增加，脾脏铁浓度降低，肝中铁调素表达降低，同时十二指肠、脾脏和肝脏中膜铁转运蛋白表达升高。在响应肝细胞铁过剩，转铁蛋白受体1表达下降，铁蛋白表达增加转基因肝脏。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。铁调素启动子活性和CCAAT/增强子结合蛋白α（C/EBP）的DNA结合活性下调伴随着C/EBP同源蛋白（C/EBP DNA结合活性的抑制剂）表达的增加，以及转基因小鼠8和14个月龄时活性氧水平的增加。结论：HCV诱导的活性氧可通过C/EBP同源蛋白抑制C/EBP α DNA结合活性下调hepcidin转录，进而导致十二指肠铁转运和巨噬细胞铁释放增加，引起肝脏铁蓄积。
Background & Aims: Despite abundant clinical evidence, the mechanisms by which hepatic iron overload develops in patients with hepatitis C virus (HCV)-associated chronic liver disease remain unknown. The aim of this study was to investigate how hepatic iron overload develops in the presence of HCV proteins. Methods: Male transgenic mice expressing the HCV polyprotein and nontransgenic control mice (C57BL/6) were assessed for iron concentrations in the liver, spleen, and serum and iron regulatory molecules in vivo and ex vivo. Results: 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. In response to hepatocellular iron excess, transferrin receptor 1 expression decreased and ferritin expression increased in the transgenic 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/EBP) were down-regulated concomitant with increased expression of C/EBP homology protein, an inhibitor of C/EBP DNA binding activity, and with increased levels of reactive oxygen species in transgenic mice at the ages of 8 and 14 months. Conclusions: HCV-induced reactive oxygen species may down-regulate hepcidin transcription through inhibition of C/EBP alpha DNA binding activity by C/EBP homology protein, which in turn leads to increased duodenal iron transport and macrophage iron release, causing hepatic iron accumulation.