Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus
Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus
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DOI：
10.1053/gast.2002.31001
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发表时间：
2002-02-01
期刊：
影响因子：
29.4
通讯作者：
Lemon, SM
中科院分区：
文献类型：
--
作者：
Lerat, H;Honda, M;Lemon, SM
背景和目标：本研究的目的是确定丙型肝炎病毒蛋白的表达是否改变肝脏的形态或功能，在没有炎症。研究方法：将编码完整病毒多聚蛋白（FL-N转基因）或病毒结构蛋白（S-N转基因）的RNA肝脏特异性表达的转基因C57 BL/6小鼠与非转基因同窝小鼠进行比较，以观察肝脏形态和功能的改变。结果如下：FL-N转录本只能通过逆转录聚合酶链反应检测到，S-N转录本在北方印迹中鉴定。病毒蛋白的丰度仅足以在S-N转基因动物中检测。在转基因肝脏中没有炎症，但表达任一转基因的小鼠发生了与年龄相关的肝脂肪变性，这在雄性中更为严重。凋亡或增殖肝细胞未显著增加。在表达任一转基因的老年雄性动物中发生肝细胞腺瘤或癌，但其发生率仅在FL-N动物中达到统计学显著性。在年龄匹配的非转基因小鼠中也没有观察到。结论：在缺乏特异性抗病毒免疫应答的情况下，病毒蛋白的组成型表达导致丙型肝炎的共同病理特征。结构蛋白的表达增强了C57 BL/6小鼠脂肪变性的低背景，而非结构蛋白的额外低水平表达增加了癌症的风险。
Background and Aims: The aim of this study was to determine whether expression of hepatitis C virus proteins alters hepatic morphology or function in the absence of inflammation. Methods: Transgenic C57BL/6 mice with liver-specific expression of RNA encoding the complete viral polyprotein (FL-N transgene) or viral structural proteins (S-N transgene) were compared with nontransgenic littermates for altered liver morphology and function. Results: FL-N transcripts were detectable only by reverse-transcription polymerase chain reaction, and S-N transcripts were Identified in Northern blots. The abundance of viral proteins was sufficient for detection only in S-N transgenic animals. There was no inflammation in transgenic livers, but mice expressing either transgene developed age-related hepatic steatosis that was more severe In males. Apoptotic or proliferating hepatocytes were not significantly increased. Hepatocellular adenoma or carcinoma developed in older male animals expressing either transgene, but their incidence reached statistical significance only In FL-N animals. Neither was ever observed In age-matched nontransgenic mice. Conclusions: Constitutive expression of viral proteins leads to common pathologic features of hepatitis C In the absence of specific anti-viral immune responses. Expression of the structural proteins enhances a low background of steatosis In C57BL/6 mice, while additional low level expression of nonstructural proteins increases the risk of cancer.