Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Translational & Stratified Medicine, Plymouth University Peninsula School of Medicine & Dentistry, United Kingdom.
J Hepatol. 2015 Apr;62(4):763-70. doi: 10.1016/j.jhep.2014.11.016. Epub 2014 Nov 21.
BACKGROUND & AIMS: Hepatitis C virus (HCV) associates with lipoproteins to form "lipoviral particles" (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance.
HCV RNA, LVP (d<1.07g/ml) and non-LVP (d>1.07g/ml) fractions, were quantified in patients with HCV-G3 (n=39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP+non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n=51).
In HCV-G3 LVP load correlated inversely with HDL-C (r=-0.421; p=0.008), and apoE (r=-0.428; p=0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R(2)=16.2%; p=0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 (p<0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1.
The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3.
丙型肝炎病毒（HCV）与脂蛋白结合形成“脂病毒颗粒”（LVPs），有助于病毒进入肝细胞。初始附着通过硫酸乙酰肝素蛋白聚糖和低密度脂蛋白受体（LDLR）发生；然后 CD81 介导附着后的事件。前蛋白转化酶枯草溶菌素 kexin9（PCSK9）增强 LDLR 的降解并调节肝脏 CD81 水平。我们测量了慢性丙型肝炎病毒基因型（G）3 感染患者的 LVP 和 PCSK9。还测量了 HCV-G1 中的 PCSK9 浓度，以间接检验 LDLR 在 LVP 清除中的作用。
通过实时 RT-PCR 定量测定 HCV-G3 患者（n=39）的 HCV RNA、LVP（d<1.07g/ml）和非-LVP（d>1.07g/ml）分数，并计算 LVP 比（LVPr；LVP/（LVP+非-LVP））。使用稳态模型评估胰岛素抵抗（HOMA-IR）评估胰岛素抵抗（IR）。通过 ELISA 测量 HCV-G3 和 HCV-G1 中的血浆 PCSK9 浓度（n=51）。
在 HCV-G3 中，LVP 载量与 HDL-C（r=-0.421；p=0.008）和载脂蛋白 E（r=-0.428；p=0.013）呈负相关。LVPr 变化超过 35 倍（中位数 0.286；范围 0.027 至 0.969）；PCSK9 是 LVPr 的最强负预测因子（R2=16.2%；p=0.012）。HOMA-IR 与 LVP 载量或 LVPr 无关。与 HCV-G1 相比，HCV-G3 中的 PCSK9 浓度显著降低（p<0.001）。在 HCV-G3 或 G1 中，PCSK9 与 LDL-C 不相关。
与 HCV-G1 相反，HCV-G3 中 LVP 与载脂蛋白 E 的负相关表明载脂蛋白 E 介导的病毒进入存在 HCV 基因型特异性差异。较低的 PCSK9 和 LDL 浓度意味着 HCV-G3 中 LDLR 活性上调。
