Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein
Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein
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DOI：
10.1053/gast.2002.30983
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发表时间：
2002-02-01
期刊：
影响因子：
29.4
通讯作者：
Weinman, SA
中科院分区：
文献类型：
--
作者：
Okuda, M;Li, K;Weinman, SA
背景与目的：慢性丙型肝炎病毒（HCV）感染引起肝损伤的机制尚不清楚。间接证据表明，氧化应激和线粒体损伤起作用。本研究的目的是确定HCV核心蛋白本身是否改变线粒体功能并导致氧化应激。方法：在3种不同的细胞系中表达HCV核心蛋白，并测定活性氧（ROS）和脂质过氧化产物。结果：核心表达均匀增加ROS。在2个诱导表达系统中，核心蛋白也增加了脂质过氧化产物，并诱导抗氧化基因的表达。线粒体电子传递抑制剂防止核心诱导的ROS增加。一部分表达的核心蛋白定位于线粒体，并与细胞色素c从线粒体到胞质组分的再分配有关。在HCV转基因小鼠中也观察到对氧化应激的敏感性，其中肝内脂质过氧化产物增加是对四氯化碳的反应。结论：在体外和体内，HCV核心蛋白表达的直接结果是发生氧化损伤，并且可能涉及核心蛋白对线粒体的直接作用。这些结果为丙型肝炎的发病机制提供了新的见解，并为研究抗氧化治疗提供了实验依据。
Background & Aims: The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood. indirect evidence suggests that oxidative stress and mitochondrial injury play a role. The aim of this study was to determine if the HCV core protein itself alters mitochondrial function and contributes to oxidative stress. Methods: HCV core protein was expressed in 3 different cell lines, and reactive oxygen species (ROS) and lipid peroxidation products were measured. Results: Core expression uniformly increased ROS. In 2 inducible expression systems, core protein also increased lipid peroxidation products and induced antioxidant gene expression as well. A mitochondrial electron transport inhibitor prevented the core-induced increase in ROS. A fraction of the expressed core protein localized to the mitochondria and was associated with redistribution of cytochrome c from mitochondrial to cytosolic fractions. Sensitivity to oxidative stress was also seen in HCV transgenic mice In which increased intrahepatic lipid peroxidation products occurred In response to carbon tetrachloride. Conclusions: Oxidative Injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria. These results provide new insight into the pathogenesis of hepatitis C and provide an experimental rationale for investigation of antioxidant therapy.