Molecular Mechanism of hepatic iron accumulation in chronic hepatitis C

慢性丙型肝炎（CH-C）常出现肝铁超载。过量的细胞铁催化羟基自由基的过度产生，最终导致细胞损伤。铁离子介导的细胞毒性在CH-C的发病和癌变过程中起重要作用。然而，肝铁蓄积在CH-C中的确切机制仍不清楚。铁调素通过下调小肠对铁离子的吸收而成为系统铁稳态的关键调节因子。我们报道了慢性HCV感染与血清铁调素水平降低相关，尽管肝脏铁蓄积（Mol Med 2007），肝铁蓄积与慢性丙型肝炎的疾病进展和干扰素/利巴韦林联合治疗的耐药性相关（J Gastroenterol Hepatol 2007），并且铁相关的肝氧化DNA损伤与慢性丙型肝炎中肝细胞癌的风险增加相关（Br J Cancer 2008）JfR 2和白细胞介素-6（IL-6）是铁调素的已知调节剂。为了阐明TfR 2和IL-6在HCV感染期间铁调素表达不足中的作用，我们使用全基因组HCV-RNA转染的肝细胞系统研究了TfR 2和IL-6表达的调节。我们的数据表明，全转铁蛋白介导的转录调控hepcidin通过TfR 2丢失，而IL-6刺激hepcidin在HCV复制子细胞中的表达，这可能部分解释了一个机制，不足hepcidin的表达和分泌在CH-C患者。

Hepatic iron overload is frequently found in chronic hepatitis C(CH-C) . Excess amount of cellular iron catalyses the over-production of hydroxyl radicals culminating in cell damage. The iron-mediated cytotoxicity plays an important role in the pathogenesis and carcinogenesis of CH-C. However, the precise mechanism of hepatic iron accumulation in CH-C is still obscure. Hepcidin acts as a key regulator of systemic iron homeostasis through down-regulating ion absorption from small intestine.We reported that chronic HCV infection is associated with lower levels of serum hepcidin despite hepatic iron accumulation(Mol Med 2007), hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C(J Gastroenterol Hepatol 2007), and that iron-related hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C(Br J Cancer 2008).Transferrin receptor 2(TfR2) and interleukin-6(IL-6)are known regulators of hepcidin. In order to clarify the roles of TfR2 and IL-6 in insufficient hepcidin expression during HCV infection, we investigated modulation of TfR2 and IL-6 expressions using a hepatocyte system transfected with full-genomic HCV-RNA. Our data showed that the holo-transferrin-mediated transcriptional regulation of hepcidin via TfR2 was lost whereas IL-6 stimulated hepcidin expression in HCV replicon cells, which may partially explain a mechanism for an insufficient hepcidin expression and secretion in CH-C patients.