Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation
Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation
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AMPK 的激活通过抑制脂质积累来限制柯萨奇病毒 B3 复制
DOI：
10.1016/j.yjmcc.2015.05.021
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发表时间：
2015
影响因子：
5
通讯作者：
Zhang Kebin
中科院分区：
文献类型：
--
作者：
Xie Wei;Wang Lei;Dai Qian;Yu Hua;He Xiaomei;Xiong Junzhi;Sheng Halei;Zhang Di;Xin Rong;Qi Yajuan;Hu Fuquan;Guo Shaodong;Zhang Kebin
柯萨奇病毒 B3 (CVB3) 是人类病毒性心肌炎的主要病原体。研究发现 CVB3 可以操纵和改变病毒复制的细胞脂质代谢。细胞 AMP 激活蛋白激酶 (AMPK) 是多种代谢途径（包括脂质代谢）的关键调节因子。在这里，我们探讨 AMPK 在 CVB3 感染中发挥的潜在作用。我们发现 Hela 细胞和原代心肌细胞中 CVB3 感染期间病毒复制会激活 AMPK。 RNA干扰介导的AMPK抑制可以增加细胞中CVB3的复制，表明AMPK有助于限制病毒复制。接下来，我们发现 CVB3 复制可以被几种不同的药理学 AMPK 激活剂抑制，包括二甲双胍、A769662 和 AICAR。并且组成型活性AMPK突变体(CA-AMPK)也可以抑制CVB3复制。此外，我们发现 CVB3 感染增加了细胞脂质水平，并表明 AMPK 激动剂 AICAR 既限制了 CVB3 复制，又通过抑制脂质合成相关基因表达来减少脂质积累。我们进一步发现CVB3感染也会诱导体内AMPK激活。广泛用于糖尿病治疗的AMPK激动剂二甲双胍可以减少病毒复制，进一步保护小鼠免受CVB3诱导的心肌炎的心肌组织学和功能改变，提高感染小鼠的存活率。最后，证明 AICAR 介导的病毒复制限制可以通过外源棕榈酸酯（脂肪酸生物合成的第一个产物）部分挽救，表明 AMPK 激活通过抑制脂质合成来限制 CVB3 感染。总而言之，本研究中的这些数据提出了一个模型，其中 AMPK 被 CVB3 感染激活，并通过抑制细胞脂质积累来限制病毒复制，并为 CVB3 相关疾病提供了一种潜在的新型治疗策略。
Coxsackievirus B3 (CVB3) is the major pathogen of human viral myocarditis. CVB3 has been found to manipulate and modify the cellular lipid metabolism for viral replication. The cellular AMP-activated protein kinase (AMPK) is a key regulator of multiple metabolic pathways, including lipid metabolism. Here we explore the potential roles AMPK plays in CVB3 infection. We found that AMPK is activated by the viral replication during CVB3 infection in Hela cells and primary myocardial cells. RNA interference mediated inhibition of AMPK could increase the CVB3 replication in cells, indicating that AMPK contributed to restricting the viral replication. Next, we showed that CVB3 replication could be inhibited by several different pharmacological AMPK activators including metformin, A769662 and AICAR. And the constitutively active AMPK mutant (CA-AMPK) could also inhibit the CVB3 replication. Furthermore, we found that CVB3 infection increased the cellular lipid levels and showed that the AMPK agonist AICAR both restricted CVB3 replication and reduced lipid accumulation through inhibiting the lipid synthesis associated gene expression. We further found that CVB3 infection would also induce AMPK activatedin vivo. The AMPK agonist metformin, which has been widely used in diabetes therapy, could decrease the viral replication and further protect the mice from myocardial histological and functional changes in CVB3 induced myocarditis, and improve the survival rate of infected mice. Lastly, it was demonstrated that the AICAR-mediated restriction of viral replication could be rescued partially by exogenous palmitate, the first product of fatty acid biosynthesis, demonstrating that AMPK activation restricted CVB3 infection through its inhibition of lipid synthesis. Taken together, these data in the present study suggest a model in which AMPK is activated by CVB3 infection and restricts viral replication by inhibiting the cellular lipid accumulation, and inform a potential novel therapeutic strategy for CVB3-associated diseases.