MicroRNA-27a Regulates Lipid Metabolism and Inhibits Hepatitis C Virus Replication in Human Hepatoma Cells
MicroRNA-27a Regulates Lipid Metabolism and Inhibits Hepatitis C Virus Replication in Human Hepatoma Cells
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DOI：
10.1128/jvi.03022-12
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发表时间：
2013-05-01
影响因子：
5.4
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
--
作者：
Shirasaki, Takayoshi;Honda, Masao;Kaneko, Shuichi
亲脂性丙型肝炎病毒（HCV）的复制和感染性受细胞脂质状态的调节。在差异表达的microRNAs（miRNAs）中，我们发现miR-27 a在HCV感染的肝脏中优先表达，而在B型肝炎病毒（HBV）感染的肝脏中则不表达。Huh-7.5细胞的基因表达谱显示，miR-27 a通过靶向脂质合成转录因子RXR α和脂质转运蛋白ATP结合盒亚家族A成员1来调节脂质代谢。此外，miR-27 a抑制了许多脂质代谢相关基因的表达，包括FXR、SREBP 1、SREBP 2、PPAR α和PPAR γ，以及ApoA 1、ApoB 100和ApoE 3，这些基因对感染性病毒颗粒的产生至关重要。miR-27 a抑制增加了细胞脂质含量，将HCV颗粒的浮力密度从1.13 g/cm 3降低到1.08 g/cm 3，并增加了病毒复制和感染性。miR-27 a过表达显著降低病毒感染性。此外，miR-27 a增强了体外干扰素（IFN）信号传导，在肝脏中表达高水平miR-27 a的患者对聚乙二醇化IFN和利巴韦林联合治疗表现出更有利的反应。有趣的是，HCV感染和脂质过载通过脂肪细胞分化转录因子C/EBP α上调miR-27 a的表达。反过来，上调的miR-27 a抑制了HCV感染和细胞中的脂质储存。因此，这种负反馈机制可能有助于维持低病毒载量，并且通过使病毒逃脱宿主免疫监视并建立持续的慢性HCV感染而对病毒有利。
The replication and infectivity of the lipotropic hepatitis C virus (HCV) are regulated by cellular lipid status. Among differentially expressed microRNAs (miRNAs), we found that miR-27a was preferentially expressed in HCV-infected liver over hepatitis B virus (HBV)-infected liver. Gene expression profiling of Huh-7.5 cells showed that miR-27a regulates lipid metabolism by targeting the lipid synthetic transcription factor RXR alpha and the lipid transporter ATP-binding cassette subfamily A member 1. In addition, miR-27a repressed the expression of many lipid metabolism-related genes, including FASN, SREBP1, SREBP2, PPAR alpha, and PPAR gamma, as well as ApoA1, ApoB100, and ApoE3, which are essential for the production of infectious viral particles. miR-27a repression increased the cellular lipid content, decreased the buoyant density of HCV particles from 1.13 to 1.08 g/cm(3), and increased viral replication and infectivity. miR-27a overexpression substantially decreased viral infectivity. Furthermore, miR-27a enhanced in vitro interferon (IFN) signaling, and patients who expressed high levels of miR-27a in the liver showed a more favorable response to pegylated IFN and ribavirin combination therapy. Interestingly, the expression of miR-27a was upregulated by HCV infection and lipid overload through the adipocyte differentiation transcription factor C/EBP alpha. In turn, upregulated miR-27a repressed HCV infection and lipid storage in cells. Thus, this negative feedback mechanism might contribute to the maintenance of a low viral load and would be beneficial to the virus by allowing it to escape host immune surveillance and establish a persistent chronic HCV infection.