中文摘要：

肝细胞脂肪变性是丙型肝炎患者的突出病理特征,但丙肝病毒（HCV）诱导脂肪变性的分子机制尚不清楚.为探究HCV非结构蛋白5A（NS5A）参与诱导脂肪变性的可能分子机制,本研究以HCV NS5A转基因小鼠为研究对象,采集3～16月龄NS5A转基因小鼠和同窝非转基因小鼠的肝组织,进行病理学检测,并用气相色谱-质谱（GC-MS）法分析脂质主要成分胆固醇酯的含量.采用RT-PCR法检测肝细胞中与脂质代谢密切相关基因肝X受体（LXR-alpha）、固醇调节元件结合蛋白（SREBP-1c）、脂肪酸合成酶（FAS）、硬脂酰辅酶A去饱和酶1（SCD1）、过氧化物酶体增殖物受体alpha（PPAR-alpha）的mRNA表达水平.结果表明,与同窝非转基因对照小鼠相比,3～5月龄NS5A转基因小鼠的肝组织没有发生显著的病理性变化,但6～16月龄的NS5A转基因小鼠的肝脏发生了显著的脂肪变性（47.1%vs 13.0%;P=0.003）.与此相一致,胆固醇酯的含量在NS5A转基因小鼠的肝脏中显著升高（P〈0.01）.RT-PCR检测结果表明,与对照小鼠相比,14月龄NS5A转基因小鼠肝组织中与脂质代谢相关的基因LXR-alpha、SREBP-1c、FAS、SCD1的mRNA表达水平显著增高（P〈0.05）,而PPAR-alpha的表达则没有显著变化（P〉0.05）.以上结果提示,NS5A在小鼠肝细胞中可能通过调高LXR-alpha/SREBP-1c信号通路相关基因的表达,进而促进脂质重新合成,诱导脂肪变性.

英文摘要：

Hepatic steatosis is a prominent pathological feature in hepatitis C patients. However, the exact molecular mechanism remains to be elucidated. To investigate the role of HCV non-structural protein 5A （NS5A） in steatosis, 3-16 month liver tissues from NS5A transgenic mice and control littermates were collected for histopathological analyses. The cholesterol ester in liver tissues were detected by GC-MS. The expression of lipid metabolism-related genes （LXR-alpha, SREBP-1c, FAS, SCD1, PPAR-alpha） were detected by RT-qPCR. The results showed that 6-16 month NS5A transgenic mice developed significant histological steatosis in liver （47. 1% versus 13.0% ; P =0. 003）, but not in 3-5 month littermates and controls. The amount of cholesterol ester was significantly higher in mice with pathological changes. The LXR-alpha, SREBP-1c, FAS, and SCD1 mRNA levels were significantly elevated in livers of 14 month-age NS5A transgenic mice （P 〈 0. 05） except for PPAR-alpha （P 〉 0.05）. The results implied that HCV NS5A promoted lipid de novo synthesis and induced hepatic steatosis by elevating the expression of LXR-alpha/SREBP-1c pathway related genes.