Iron metabolic disorder and hepatocarcinogenesis in hepatitis C

尽管有证据表明慢性丙型肝炎患者存在肝脏铁超载，但目前尚不清楚铁超载是否与肝癌的发生有关，以及肝铁超载是如何发生的。本研究的目的是确定铁超载是否与肝细胞癌的发生有关，并阐明肝脏铁超载的发生机制。肝脏铁超载与肝癌发生的关系：饲喂过量铁饮食的小鼠的肝铁浓度与慢性丙型肝炎患者相当。转基因和非转基因肝脏没有炎症反应。与其他三组小鼠相比，高铁饲料喂养的转基因小鼠在6个月时表现出明显的肝脏脂肪变性，包括小叶中心型微泡、线粒体超微结构变化和脂肪酸降解活性降低，肝脏脂质过氧化产物和8-羟基-2‘-脱氧…含量增加。在开始喂养的12个月后，更多的奥辛。高铁饲料喂养的小鼠的增殖肝细胞数量显著增加，但转基因和非转基因小鼠之间没有差异。在11只转基因小鼠中，有5只(45%)在开始喂养12个月后出现了包括肝癌在内的肝脏肿瘤，但在其他组小鼠中没有发生。肝脏铁超载的发生机制：转基因小鼠肝脏和血清中铁浓度升高，脾中铁浓度降低，肝组织中海普西丁表达降低，同时十二指肠、脾和肝脏中铁转运蛋白表达增强。转基因小鼠在肝脏中没有炎症反应，但保留了在内毒素诱导的促炎细胞因子反应中产生海普西丁的能力。在8和14个月龄的转基因小鼠中，随着C/EBPDNA结合活性抑制物C/EBPDNA同源蛋白(CHOP)的表达增加，CCAAT/增强子结合蛋白α(C/EBPDNA)的启动子活性和α的DNA结合活性也随之下调，并伴随着活性氧(ROS)水平的升高。较少

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