Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
Liver Int. 2018 May;38(5):803-812. doi: 10.1111/liv.13581. Epub 2017 Oct 4.
BACKGROUND & AIMS: Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed.
To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied.
Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression.
Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression.
肝脂肪变性是慢性丙型肝炎患者的常见特征。先前的报告表明，丙型肝炎病毒核心编码序列（丙型肝炎病毒基因型 3a 和 1b）的过表达显著诱导细胞内甘油三酯积累。然而，其潜在机制尚未被揭示。
为了研究 Sirt1 是否参与丙型肝炎病毒介导的肝脂肪变性，我们在 HepG2 细胞中过表达丙型肝炎病毒核心 1b 蛋白和 Sirt1，并敲低 Sirt1。为了验证细胞实验的结果，我们使用慢病毒介导的丙型肝炎病毒核心 1b 过表达研究了肝特异性 Sirt1 KO 小鼠。
我们的结果表明，丙型肝炎病毒核心 1b 蛋白过表达导致 HepG2 细胞中甘油三酯的积累。值得注意的是，丙型肝炎病毒核心 1b 过表达显著增加了 PPARγ2 的 mRNA 和蛋白水平的表达。Sirt1 的蛋白表达是 PPARγ2 的上游调节剂，丙型肝炎病毒核心 1b 过表达后也显著增加。此外，Sirt1 的过表达或敲低单独足以调节 p300 介导的 PPARγ2 去乙酰化。体内研究表明，通过下调 PPARγ2 表达，肝特异性 Sirt1 KO 小鼠中丙型肝炎病毒核心蛋白 1b 诱导的肝脂肪变性减弱。
Sirt1 通过调节 PPARγ2 的表达介导丙型肝炎病毒核心蛋白 1b 诱导的肝脂肪变性。
