Division of Clinical Pathology, University Hospital, Geneva, Switzerland.
Hepatology. 2011 Jul;54(1):38-49. doi: 10.1002/hep.24340.
Hepatitis C virus (HCV) perturbs the host's lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV-induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down-regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down-regulated PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN messenger RNA translation. PTEN down-regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down-regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN-dependent mechanisms are involved in this process.
The down-regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a-induced formation of large lipid droplets in hepatocytes.
丙型肝炎病毒（HCV）扰乱宿主的脂质代谢，常导致肝脂肪变性。在非酒精性脂肪性肝病中，第 10 号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）在肝内的下调是导致脂肪变性及其向纤维化和肝细胞癌进展的关键机制。然而，HCV 感染是否通过 PTEN 依赖性机制引发大脂滴的形成尚不清楚。我们评估了感染 HCV 基因型 1 或 3 且伴有或不伴有脂肪变性的患者肝脏中的 PTEN 表达。我们进一步用感染了 1b 型或 3a 型 HCV 核心蛋白的肝癌细胞在体外研究了 PTEN 在 HCV 诱导的脂滴形成中的作用。我们的数据表明，在感染 3a 型基因型的脂肪变性患者中，PTEN 表达在转录后水平下调。同样，HCV 基因型 3a 核心蛋白（而非 1b）的体外表达（通常导致大脂滴的出现）通过涉及 microRNA 依赖性 PTEN mRNA 翻译阻断的机制下调了 PTEN 表达。PTEN 下调继而促进胰岛素受体底物 1（IRS1）表达减少。有趣的是，PTEN 或 IRS1 的过表达均可阻止大脂滴的形成，这表明下调 PTEN 和 IRS1 均会影响脂滴的形成。然而，IRS1 的敲低本身不会改变脂滴的形态，这表明其他依赖于 PTEN 的机制也参与了这一过程。
PTEN 和 IRS1 的下调是丙型肝炎病毒基因型 3a 诱导肝细胞中大脂滴形成的关键事件。
