Institute of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11549-54. doi: 10.1073/pnas.0912426107. Epub 2010 Jun 7.
Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.
丙型肝炎病毒（HCV）感染与脂质和葡萄糖代谢的失调有关。这些干扰不仅有助于病毒复制，还影响与病毒相关的发病机制，包括脂肪变性、胰岛素抵抗和 2 型糖尿病。AMP 激活的蛋白激酶（AMPK）在脂质和葡萄糖代谢的调节中起着关键作用。我们在这里表明，在感染 HCV 的细胞或携带 HCV 亚基因组复制子的细胞中，AMPK 在苏氨酸 172 位的磷酸化和伴随的 AMPK 活性显著降低。我们证明这种效应是通过丝氨酸/苏氨酸激酶蛋白激酶 B 的激活介导的，该激酶通过磷酸化丝氨酸 485 来抑制 AMPK。这种抑制的生理意义通过观察到药物恢复 AMPK 活性不仅消除了在病毒感染和亚基因组复制子携带的细胞中观察到的脂质积累，而且有效地抑制了病毒复制来证明。这些数据表明，抑制 AMPK 是 HCV 复制所必需的，而恢复 AMPK 活性可能为急需的抗 HCV 治疗提供一个目标。
