Department of Microbiology and Immunobiology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
J Am Chem Soc. 2012 Apr 25;134(16):6896-9. doi: 10.1021/ja207391q. Epub 2012 Apr 11.
Hepatitis C virus (HCV) infection has been clinically associated with serum lipid abnormalities, yet our understanding of the effects of HCV on host lipid metabolism and conversely the function of individual lipids in HCV replication remains incomplete. Using liquid chromatography-mass spectrometry metabolite profiling of the HCV JFH1 cell culture infection model, we identified a significant steady-state accumulation of desmosterol, an immediate precursor to cholesterol. Pharmacological inhibition or RNAi-mediated depletion of DHCR7 significantly reduced steady-state HCV protein expression and viral genomic RNA. Moreover, this effect was reversed when cultures were supplemented with exogenous desmosterol. Together, these observations suggest an intimate connection between HCV replication and desmosterol homeostasis and that the enzymes responsible for synthesis of desmosterol may be novel targets for antiviral design.
丙型肝炎病毒 (HCV) 感染与血清脂质异常在临床上有关联，然而，我们对 HCV 对宿主脂质代谢的影响以及相反地，个别脂质在 HCV 复制中的功能的理解仍不完整。使用 HCV JFH1 细胞培养感染模型的液相色谱-质谱代谢物分析，我们发现甾醇前体去甲胆固醇显著稳定积累。DHCR7 的药理学抑制或 RNAi 介导的耗竭显著降低了 HCV 蛋白表达和病毒基因组 RNA 的稳定状态。此外，当培养物用外源性去甲胆固醇补充时，这种作用得到逆转。总之，这些观察结果表明 HCV 复制与去甲胆固醇稳态之间存在密切联系，负责去甲胆固醇合成的酶可能是抗病毒设计的新靶点。
