Molecular Mechanism of hepatic iron accumulation in chronic hepatitis C

慢性丙型肝炎肝铁蓄积的分子机制

• 批准号: 18590728
• 负责人: KOBAYASHI Yoshinao
• 金额: $ 2.47万
• 依托单位: Mie 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-18590728/
• 关键词: chronic hepatitis C; iron accumulation; hepcidin; transferrin receptor; oxdative stress; reactive oxygen species; carcinogenesis; トランスフェリ、ンレセプター; C型肝炎ウイルス; 8-イソプロスタン; 8-hydroxy-2'-deoxyguanosine; hepcidine; 鉄; トランスフェリン

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.

肝铁超载常见于慢性丙型肝炎（CH-C）。过量的细胞铁催化羟基自由基的过量产生，最终导致细胞损伤。铁介导的细胞毒性在CH-C的发病和癌变过程中起重要作用。然而，肝铁积累在CH-C中的确切机制仍不清楚。Hepcidin通过下调小肠对离子的吸收，起到调节全身铁稳态的关键作用。我们报道了慢性HCV感染与低水平血清hepcidin相关，尽管肝铁积累（Mol Med 2007），肝铁积累与慢性丙型肝炎的疾病进展和对干扰素/利巴韦林联合治疗的耐药性相关（J Gastroenterol Hepatol 2007），铁相关的肝脏氧化DNA损伤与慢性丙型肝炎肝细胞癌的风险增加相关（Br J Cancer 2008）。转铁蛋白受体2（TfR2）和白细胞介素-6（IL-6）是已知的hepcidin的调节因子。为了阐明TfR2和IL-6在HCV感染期间hepcidin表达不足中的作用，我们使用转染全基因组HCV- rna的肝细胞系统研究了TfR2和IL-6表达的调节。我们的数据显示，在HCV复制子细胞中，全转铁蛋白介导的通过TfR2介导的hepcidin转录调控丢失，而IL-6则刺激hepcidin表达，这可能部分解释了CH-C患者hepcidin表达和分泌不足的机制。

项目成果

C型肝炎ウイルス遺伝子導入肝細胞におけるトランスフェリンレセプター2の発現調節

丙型肝炎病毒转染肝细胞中转铁蛋白受体2表达的调控

• 发表时间: 2007
• 作者: 小林由直;小西正芳;垣内雅彦;渡邉省三;他
• 通讯作者: 他

Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C.

• DOI: 10.1038/sj.bjc.6604204
• 发表时间: 2008-02-12
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Tanaka, H.;Fujita, N.;Sugimoto, R.;Urawa, N.;Horiike, S.;Kobayashi, Y.;Iwasa, M.;Ma, N.;Kawanishi, S.;Watanabe, S.;Kaito, M.;Takei, Y.
• 通讯作者: Takei, Y.

Impaired transcriptional regulation of transferrin receptor 2 and its role in insufficient hepcidin expression in HCV-Study transfected cells

转铁蛋白受体 2 的转录调节受损及其在 HCV-Study 转染细胞中铁调素表达不足中的作用

• 发表时间: 2007
• 作者: Kobayashi;Y;Fujita;N;et. al.
• 通讯作者: et. al.

Increased lipid peroxidation in patients with non-alcholic fatty liver desease and chronic hepatitis C as measured by the plasma level of 8-isoprostane

通过血浆 8-异前列烷水平测量，非酒精性脂肪肝病和慢性丙型肝炎患者脂质过氧化增加

• 发表时间: 2006
• 期刊: Journal of Gastroenterology and Hepatology 21,12
• 作者: Konishi M;Iwasa M;Araki J;Kobayashi Y;Katsuki A et al.
• 通讯作者: Katsuki A et al.

C型慢性肝炎における肝内鉄過剰-酸化ストレスの肝細胞癌発生への関与

慢性丙型肝炎肝内铁超负荷——氧化应激参与肝细胞癌的发展

• 发表时间: 2007
• 作者: 藤田 尚己、小林 由直;他
• 通讯作者: 他