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

Lookup NU author(s): Dr Simon Bridge, Dr David Sheridan, Dr Daniel Felmlee, Fiona Fenwick, Dr Clare Lanyon, Professor Geoff Toms, Dr R Neely, Professor Margaret Bassendine

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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) and non-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 (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.Conclusions: 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. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Publication metadata

Author(s): Bridge SH, Sheridan DA, Felmlee DJ, Crossey MME, Fenwick FI, Lanyon CV, Dubuc G, Seidah NG, Davignon J, Thomas HC, Taylor-Robinson SD, Toms GL, Neely RDG, Bassendine MF

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2015

Volume: 62

Issue: 4

Pages: 763-770

Print publication date: 01/04/2015

Online publication date: 21/11/2014

Acceptance date: 12/11/2014

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.jhep.2014.11.016

DOI: 10.1016/j.jhep.2014.11.016


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