LXR-alpha/SREBP-1c通路参与HCV NS5A诱导的肝细胞脂质代谢紊乱

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(P0.01).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(P0.05),而PPAR-alpha的表达则没有显著变化(P0.05).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.

LXR-alpha/SREBP-1c Pathway Involved in Lipid Metabolism Disorders of hepatocytes Induced by HCV NS5A

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.