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

Bridge, Simon, Sheridan, David, Felmlee, Daniel, Crossey, Mary, Fenwick, Fiona, Lanyon, Clare, Dubuc, Geneviève, Seidah, Nabil, Davignon, Jean, Thomas, Howard, Taylor-Robinson, Simon, Toms, Geoffrey, Neely, Robert Dermot and Bassendine, Margaret (2015) PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism. Journal of Hepatology, 62 (4). pp. 763-770. ISSN 0270-9319

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

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 (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 <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.

Item Type: Article
Additional Information: Available online ahead of print.
Uncontrolled Keywords: Apolipoprotein A1, Apolipoprotein E, HCV lipoviral particles, HDL-C, Low-density lipoprotein receptor, PCSK9
Subjects: C500 Microbiology
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Nicola King
Date Deposited: 11 Dec 2014 12:09
Last Modified: 24 Oct 2017 11:24
URI: http://nrl.northumbria.ac.uk/id/eprint/18462

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