Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway
Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway
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DOI：
10.1128/jvi.00146-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Hotta, Hak
中科院分区：
文献类型：
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作者：
Deng, Lin;Shoji, Ikuo;Hotta, Hak
慢性丙型肝炎病毒(丙型肝炎病毒)感染通常与2型糖尿病有关。然而，这种联系背后的确切机制仍不清楚。在这里，使用携带丙型肝炎病毒1b RNA复制子的Huh-7.5细胞或感染丙型肝炎病毒2a的细胞，我们发现丙型肝炎病毒转录上调了磷酸烯醇式丙酮酸羧激酶(PEPCK)和葡萄糖6-磷酸酶(G6Pase)的基因，这两种酶是肝脏糖异生的限速酶。通过这种方式，丙型肝炎病毒促进了细胞葡萄糖6-磷酸(G6P)和葡萄糖的产生。PEPCK和G6Pase基因的表达受转录因子叉头盒O1(FoxO1)调控。我们观察到，尽管FoxO1的表达水平和蛋白水平都没有受到丙型肝炎病毒的影响，但在丙型肝炎病毒感染的细胞中，Ser319处的FoxO1的磷酸化水平明显低于对照细胞，导致FoxO1的核积累增加，这是维持其转录活性所必需的。FoxO1磷酸化水平的降低不太可能是通过Akt失活来调节的，因为我们观察到在丙型肝炎病毒感染的细胞中，Ser473处Akt的磷酸化水平比对照细胞高。通过使用c-jun氨基末端激酶(JNK)和活性氧自由基(ROS)的特异性抑制剂，我们证明了丙型肝炎病毒感染通过增加线粒体ROS产生而诱导JNK激活，导致FoxO1磷酸化降低，FoxO1核积聚，最终增加葡萄糖产生。我们还发现，丙型肝炎病毒NS5A介导的ROS产生和JNK激活增加，这与FoxO1依赖的糖异生增加直接相关。综上所述，这些观察表明，丙型肝炎病毒通过NS5A介导的FoxO1依赖的途径促进肝脏糖异生。
Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCV-infected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway.