Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Medical College, Fudan University, Shanghai, China.
Cell Microbiol. 2020 Feb;22(2):e13131. doi: 10.1111/cmi.13131. Epub 2019 Dec 4.
A growing consensus indicates that host metabolism plays a vital role in viral infections. Hepatitis B virus (HBV) infection occurs in hepatocytes with active glucose metabolism and may be regulated by cellular metabolism. We addressed the question whether and how glucose regulates HBV replication in hepatocytes. The low glucose concentration at 5 mM significantly promoted HBV replication via enhanced transcription and autophagy when compared with higher glucose concentrations (10 and 25 mM). At low glucose concentration, AMPK activity was increased and led to ULK1 phosphorylation at Ser 555 and LC3-II accumulation. By contrast, the mTOR pathway was activated by high glucose concentrations, resulting in reduced HBV replication. mTOR inhibition by rapamycin reversed negative effects of high glucose concentrations on HBV replication, suggesting that low glucose concentration promotes HBV replication by stimulating the AMPK/mTOR-ULK1-autophagy axis. Consistently, we found that glucose transporters inhibition using phloretin also enhanced HBV replication via increased AMPK/mTOR-ULK1-induced autophagy. Surprisingly, the glucose analogue 2-deoxy-D-glucose reduced HBV replication through activating the Akt/mTOR signalling pathway also at the low glucose concentrations. Our study reveals that glucose is an important factor for the HBV life cycle by regulating HBV transcription and posttranscriptional steps of HBV replication via cellular autophagy.
越来越多的共识表明，宿主代谢在病毒感染中起着至关重要的作用。乙型肝炎病毒 (HBV) 感染发生在代谢活跃的肝细胞中，可能受到细胞代谢的调节。我们探讨了葡萄糖是否以及如何调节肝细胞中的 HBV 复制。与高浓度葡萄糖（10 和 25mM）相比，低浓度葡萄糖（5mM）通过增强转录和自噬显著促进 HBV 复制。在低葡萄糖浓度下，AMPK 活性增加，导致 ULK1 在 Ser555 位点磷酸化和 LC3-II 积累。相比之下，高葡萄糖浓度激活了 mTOR 通路，导致 HBV 复制减少。雷帕霉素抑制 mTOR 可逆转高葡萄糖浓度对 HBV 复制的负效应，表明低葡萄糖浓度通过刺激 AMPK/mTOR-ULK1-自噬轴促进 HBV 复制。一致地，我们发现使用根皮苷抑制葡萄糖转运蛋白也通过增加 AMPK/mTOR-ULK1 诱导的自噬增强 HBV 复制。令人惊讶的是，葡萄糖类似物 2-脱氧-D-葡萄糖也通过激活 Akt/mTOR 信号通路在低葡萄糖浓度下降低 HBV 复制。我们的研究表明，葡萄糖是 HBV 生命周期的一个重要因素，通过调节 HBV 转录和 HBV 复制的转录后步骤来调节 HBV 复制。
