PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism

Simon Bridge, David Sheridan, Daniel Felmlee, Mary Crossey, Fiona Fenwick, Clare Lanyon, Geneviève Dubuc, Nabil Seidah, Jean Davignon, Howard Thomas, Simon Taylor-Robinson, Geoffrey Toms, Robert Dermot Neely, Margaret Bassendine

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

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. Methods HCV RNA, LVP (d 1.07 g/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). Results 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 (R2 = 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
Original languageEnglish
Pages (from-to)763-770
JournalJournal of Hepatology
Volume62
Issue number4
Early online date21 Nov 2014
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • Apolipoprotein A1
  • Apolipoprotein E
  • HCV lipoviral particles
  • HDL-C
  • Low-density lipoprotein receptor
  • PCSK9

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