近日，中国科学院广州生物医药与健康研究院在丙型肝炎病毒致病性和感染性研究方面取得新进展，相关研究成果于5月14日在线发表在《病毒学杂志》（Journal of Virology）上。

　　据WHO最新统计，目前全球约1.85亿人被丙型肝炎病毒（HCV）慢性感染；我国的丙肝病毒携带率高达3.5%，并且发病率逐年增加。HCV感染后不仅会导致慢性肝炎、脂肪肝、肝硬化直至肝癌等肝脏疾病，还会导致代谢性疾病的发生（例如胰岛素抵抗和二型糖尿病）。而HCV感染进行自身复制及导致代谢疾病发生的机制还有待于深入研究。

    广州生物院彭涛实验室发现，HCV感染同时上调了WT-PGC-1α 和L-PGC-1α的表达，上调的PGC-1α 一方面促进HCV病毒的产生，一方面导致HCV诱发的胰岛素抵抗；HCV感染对PGC-1α的上调依赖于HCV的RNA复制，内质网应激（ER stress）介导了该上调作用。

　　PGC-1α作为共激活因子，通过与其他转录因子的相互作用实现对下游靶基因的转录调控。作为能量代谢的关键调控因子，PGC-1α在肝脏中参与了对糖异生和脂肪酸氧化的调控。2011年报道发现了人肝脏中PGC-1α新的异构体，即L-PGC-1α；相应地之前经典的PGC-1α被称为WT-PGC-1α。

    彭涛实验室的研究结果显示，HCV感染可以上调上述两种形式PGC-1α 的表达，ER stress 介导了HCV感染对PGC-1α的上调；结果还显示，ER stress抑制剂PBA在抑制HCV感染对PGC-1α 上调的同时，亦可以抑制HCV病毒的产生（PBA已被美国FDA批准用于治疗尿素循环异常）。

    该研究成果不仅在机制上深化了人们对HCV致病性和感染性的认识，还在应用上提示可将HCV-ERstress-PGC-1α 信号通路作为治疗HCV感染以及相关胰岛素抵抗的潜在药物靶标。

原文摘要：

Endoplasmic reticulum stress links hepatitis C virus RNA replication to WT-PGC-1α/L-PGC-1α upregulation

Hepatitis C virus (HCV) causes not only severe liver problems but also extra hepatic manifestations, such as insulin resistance (IR). Wild-type (WT)-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant-negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1α was mediated by the phosphorylation of cAMP-response element-binding protein (CREB) whereas that of L-PGC-1α was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress and pharmacological induction of ER stress upregulated WT-PGC-1α/L-PGC-1α and phosphorylated CREB. By contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway and both PGC-1α isoforms promote HCV production in turn.

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