Acute expression of hepatitis C core protein in adult mouse liver: Mitochondrial stress and apoptosis
Acute expression of hepatitis C core protein in adult mouse liver: Mitochondrial stress and apoptosis
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DOI：
10.1080/00365520701875987
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发表时间：
2008-01-01
影响因子：
1.9
通讯作者：
Lin, Deng-Yn
中科院分区：
文献类型：
--
作者：
Chang, Ming-Ling;Chen, Jeng-Chang;Lin, Deng-Yn
客观的。在丙型肝炎病毒 (HCV) 感染中，30-40% 的病例会自发清除病毒。相比之下，在慢性感染中，这种情况很少见。急性疾病中病毒清除的基础尚不清楚。尽管细胞免疫反应已被详细研究，但关于病毒结构蛋白（例如核心蛋白）的作用的数据很少。本研究的目的是通过使用新的转基因小鼠系来研究成年小鼠肝细胞中从头产生的核心的影响，其中 HCV 核心的表达受四环素 (tet-off) 调节。材料和方法。在这项工作中，创建了具有条件性 HCV 核心的转基因小鼠，以研究 HCV 核心蛋白在成熟肝脏中的急性表达。监测核心的亚细胞分布、肝细胞氧化应激和凋亡。结果。核心蛋白很容易检测到，并且与细胞质脂质囊泡、内质网和线粒体密切相关。硫氧还蛋白-2 (trx2) 的减少证明了线粒体氧化应激。同时，caspase-3 活性和 TUNEL 增加，并且随着时间的推移，肝脏中核心蛋白的水平下降。结论。开发了 HCV 核心蛋白条件转基因小鼠，该蛋白很容易检测到，并且在形态学上与个体肝细胞的脂肪变性相关。核心蛋白的急性表达会导致线粒体应激，这一点可以通过 trx2 的减少和核心阳性肝细胞的凋亡来证明。我们推测这些事件可能与急性丙型肝炎期间的病毒清除有关，既减轻了肝脏中的病毒负担，又有效地启动了免疫反应。
Objective. In infection with hepatitis C virus (HCV), spontaneous clearance of the virus occurs in 30-40% of cases. By contrast, in chronic infection, this is rare. The basis for viral clearance in acute disease is unknown. Whereas cellular immune responses have been studied in detail, few data exist on the role of viral structural proteins, such as the core protein. The purpose of this study was to investigate the effects of core produced de novo within adult mouse hepatocytes by using a new transgenic mouse line in which expression of HCV core is regulated by tetracycline (tet-off). Material and methods. In this work, transgenic mice with conditional HCV core were created, to study the acute expression of HCV core protein in the context of the mature liver. The subcellular distribution of the core, hepatocellular oxidative stress and apoptosis were monitored. Results. Core protein is readily detectable and strongly associated with cytoplasmic lipid vesicles, endoplasmic reticulum and mitochondria. Mitochondrial oxidative stress was evidenced by a reduction in thioredoxin-2 (trx2). Concurrently, caspase-3 activity and TUNEL increased and, over time, the level of core protein in the liver declined. Conclusions. Mice that are conditionally transgenic for HCV core protein, which is readily detected and morphologically associated with steatosis in individual hepatocytes, were developed. Acute expression of core protein causes mitochondrial stress, as demonstrated by a reduction in trx2 and in the apoptosis of core-positive hepatocytes. We speculate that these events could be involved in the clearance of virus during acute hepatitis C, by both reducing the burden of virus in the liver and effectively priming the immune response.