Pyruvate dehydrogenase kinase regulates hepatitis C virus replication.
Pyruvate dehydrogenase kinase regulates hepatitis C virus replication.
复制标题
DOI：
10.1038/srep30846
复制
发表时间：
2016-07-29
影响因子：
4.6
通讯作者：
Park KG
中科院分区：
文献类型：
--
作者：
Jung GS;Jeon JH;Choi YK;Jang SY;Park SY;Kim SW;Byun JK;Kim MK;Lee S;Shin EC;Lee IK;Kang YN;Park KG
在复制过程中，丙型肝炎病毒（HCV）利用其宿主细胞产生的大分子。这一过程需要宿主细胞代谢重编程，以促进有氧糖酵解水平的提高。因此，我们评估了丙酮酸脱氢酶激酶（PDK），一种促进有氧糖酵解的线粒体酶，是否可以调节HCV复制。比较了HCV感染和未感染的人肝脏以及感染或未感染HCV的Huh-7.5细胞中c-Myc、缺氧诱导因子-1 α（HIF-1α）、PDK 1、PDK 3、葡萄糖激酶和丝氨酸生物合成酶的水平。HCV感染的人肝和肝细胞中c-Myc、HIF-1α和糖酵解酶的蛋白和mRNA表达显著高于未感染的对照组。这种增加伴随着丝氨酸生物合成酶的上调，这表明细胞代谢被改变为促进HCV复制所必需的核苷酸合成。JQ 1（一种c-Myc抑制剂）和二氯乙酸（DCA）（一种PDK抑制剂）可降低HCV感染肝细胞中糖酵解和丝氨酸合成酶的表达，从而抑制病毒复制。此外，当与IFN-α或病毒唑联合给药时，DCA进一步抑制病毒复制。总之，HCV重编程宿主细胞代谢以有利于糖酵解和丝氨酸生物合成;这至少部分地由增加的PDK活性介导，其提供了过量的核苷酸前体。因此，阻断PDK活性可能对HCV复制具有治疗益处。
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication.