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J Virol:发现肝细胞核因子-4α(HNF4α)在丙型肝炎病毒包装释放过程中的作用

来源:中国科学院广州生物医药与健康研究院 2013-11-19 18:44

丙型肝炎病毒(HCV)全球慢性感染人数约1.7亿,我国处于丙型肝炎高发区,新发丙型肝炎病例逐年递增。HCV感染后约50-80%的患者会建立慢性感染,会导致慢性肝炎、脂肪肝、肝硬化直至肝癌等疾病。HCV的生活周期与宿主的脂代谢关系密切,尤其是HCV可以“挟持”肝细胞极低密度脂蛋白(VLDL)合成和分泌的过程用以促进自身的包装和释放。而HCV利用VLDL通路的机制尚不清楚。中科院广州生物医药与健康研究院彭涛实验室联合陈凌实验室近期发现,人肝细胞核因子-4α(HNF4α)在HCV的包装和释放过程中发挥重要作用,其下游因子磷脂酶A2 GXIIB(PLA2GXIIB)和微粒体甘油三酯转运蛋白(MTP)共同参与其对HCV包装和释放过程的调控。该研究提示了HCV可能利用HNF4α来挟持VLDL通路为己所用。相关研究成果已于近期在病毒学杂志(Journal of Virology)上在线发表。

HNF4α是表达量最高的肝细胞特异转录因子,它在肝脏的分化、成熟肝细胞的功能维持尤其是脂代谢方面发挥重要作用,HNF4α可以通过调控VLDL合成和分泌的方式维持肝脏及血液中的脂质平衡。彭涛实验室发表的结果显示HCV感染可以上调HNF4α的表达,继而增加感染性病毒的产生。HNF4α的抑制剂或siRNA介导的敲低作用会显着降低感染性HCV的产生。该研究成果不仅可以深化对HCV-宿主相互作用的认识,并且提示了HNF4α或可以作为治疗HCV感染的潜在的宿主靶标。(生物谷Bioon.com)

 

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Journal of Virology    doi:10.1128/JVI.02068-13

Hepatocyte Nuclear Factor-4 Alpha (HNF4α) and Downstream Secreted Phospholipase A2 GXIIB (PLA2GXIIB) Regulate Production of Infectious Hepatitis C Virus

Xinlei Li, Hanfang Jiang, Linbing Qu, Wenxia Yao, Hua Cai, Ling Chen and Tao Peng

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. The life cycle of HCV is closely associated with the metabolism of lipids, especially very-low-density lipoprotein (VLDL) in hepatocytes. Hepatocyte nuclear factor-4α (HNF4α), the most abundant transcription factor in the liver, regulates the VLDL secretory pathway. However, the effects of HNF4α on HCV life cycle are unclear. In this study, we investigated the regulatory effects of HNF4α on HCV assembly and secretion. HCV in HNF4α-deficient hepatocytes showed reduced assembly and secretion but unchanged entry and RNA replication. Bezafibrate, a chemical inhibitor of HNF4α, suppressed HCV assembly and secretion. HNF4α down-regulation resulted in rearrangement of cytosolic lipid droplets (LDs), as evidenced by the aggregation of large LDs and distorted cytosolic distribution. Phospholipase A2 GXIIB (PLA2GXIIB), an HNF4α-regulated factor involved in VLDL secretion, was found to be crucial in HCV secretion. PLA2GXIIB expression was up-regulated in hepatocytes harboring HCV subgenomic replicons or in HCV-infected hepatocytes. This up-regulation was transcriptionally controlled in an HNF4α-dependent manner after HCV infection. Furthermore, PLA2GXIIB combined with microsomal triglyceride transfer protein was found to be responsible for the regulation of HNF4α-induced HCV infectivity. These results suggest that HNF4α and its downstream PLA2GXIIB are important factors affecting the late stage of HCV life cycle, and may serve as potential drug targets for the treatment of HCV infection.

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