Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan.
Division of Infectious Disease Control, Graduate School of Medicine, Kobe University, Kobe, Japan.
Microbiol Immunol. 2024 Oct;68(10):359-370. doi: 10.1111/1348-0421.13166. Epub 2024 Jul 29.
Statins, such as lovastatin, have been known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5-20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular-signal-regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose-dependent manner. The lovastatin-mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8-92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol-lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG-CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG-CoA reductase inhibition and ERK5 activation.
他汀类药物，如洛伐他汀，已被证实可抑制 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶。有报道称，他汀类药物可适度抑制携带 HCV RNA 复制子的培养细胞中的丙型肝炎病毒（HCV）复制。我们在此报告使用 HCV 细胞培养（HCVcc）系统，发现高浓度的洛伐他汀（5-20μg/mL）可使培养上清液中 HCV 感染性颗粒（病毒粒子）的释放显著增加多达 40 倍，而不会增强 HCV RNA 复制、HCV 蛋白合成或细胞内 HCV 病毒粒子组装。我们还发现，洛伐他汀以剂量依赖性方式增加感染和未感染细胞中细胞外信号调节激酶 5（ERK5）的磷酸化（激活）水平。洛伐他汀介导的 HCV 病毒粒子释放增加可部分被选择性 ERK5 抑制剂 BIX02189 和 XMD8-92 或通过小干扰 RNA（siRNA）敲低 ERK5 逆转。此外，我们证明其他降低胆固醇的他汀类药物，而不是不能抑制 HMG-CoA 还原酶和激活 ERK5 的脱水洛伐他汀，也能以与洛伐他汀相同的程度增强 HCV 病毒粒子的释放。这些结果共同表明，他汀类药物通过抑制 HMG-CoA 还原酶和激活 ERK5，显著增强感染细胞中 HCV 病毒粒子的释放。
