Objective HCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle. Design Huh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation. Results Upon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity. Conclusions We have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.

中文翻译：

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溶血磷脂酰胆碱酰基转移酶 1 被丙型肝炎病毒下调：对脂病毒颗粒产生的影响

目的 HCV 与肝脏脂质代谢密切相关，致力于以富含三酰甘油的极低密度脂蛋白 (VLDL) 形式储存在脂滴 (LD) 中的三酰甘油流出：(i) 最具传染性的 HCV 颗粒是由于与富含甘油三酯的脂蛋白相关而密度最低的那些和 (ii) HCV 感染患者经常发生肝脂肪变性（甘油三酯储存增加）。最近鉴定的溶血磷脂酰胆碱酰基转移酶 1 (LPCAT1) 作为 LD 磷脂重塑酶促使我们研究其在肝脏脂质代谢和 HCV 感染循环中的作用。设计 Huh-7.5.1 细胞和原代人肝细胞 (PHH) 被 JFH1-HCV 感染。LPCAT1 耗竭是通过 RNA 干扰实现的。监测细胞的 LPCAT1 表达，脂质代谢和 HCV 产生和传染性。通过等密度超速离心评估病毒颗粒的密度。结果 HCV 感染后，Huh-7.5.1 细胞和 PHH 的 LPCAT1 转录物和蛋白质水平降低，与转录下调一致。在幼稚或感染的 Huh-7.5.1 细胞中 LPCAT1 耗竭导致脂质代谢改变，其特征是 LD 重塑、甘油三酯储存增加和 VLDL 分泌增加。在受感染的 Huh-7.5.1 细胞或 PHH 中，LPCAT1 消耗增加了密度最低和传染性最高的病毒颗粒的产生。结论 我们已经确定 LPCAT1 是 HCV 下调的肝脏脂质代谢的调节剂，这似乎是一种增加三酰甘油含量并因此增加病毒颗粒感染性的病毒策略。