title: PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism.
abstract: OBJECTIVE
  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<1.07g/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).
  
  
  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.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom. Electronic address: simon.bridge@northumbria.ac.uk.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Bridge
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Sheridan
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Inserm U1110, University of Strasbourg and Center for Liver and Digestive Diseases, Strasbourg University Hospitals, 3 Rue Koeberlé, F-67000 Strasbourg, France.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Felmlee
authors.affiliation: Liver Unit, Department of Medicine, Imperial College London, St Mary's Hospital Campus, Praed Street, London, United Kingdom.
authors.forename: Mary M E
authors.initials: MM
authors.lastname: Crossey
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Fiona I
authors.initials: FI
authors.lastname: Fenwick
authors.affiliation: Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Lanyon
authors.affiliation: Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montréal (IRCM), Montréal, Canada; University of Montréal, Montréal, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dubuc
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montréal, Montréal, Canada; University of Montréal, Montréal, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montréal (IRCM), Montréal, Canada; University of Montréal, Montréal, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Davignon
authors.affiliation: Liver Unit, Department of Medicine, Imperial College London, St Mary's Hospital Campus, Praed Street, London, United Kingdom.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.affiliation: Liver Unit, Department of Medicine, Imperial College London, St Mary's Hospital Campus, Praed Street, London, United Kingdom.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Toms
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Clinical Biochemistry, Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, United Kingdom.
authors.forename: R Dermot G
authors.initials: RD
authors.lastname: Neely
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: margaret.bassendine@newcastle.ac.uk.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Bassendine
mesh_terms: D000328:Adult; D001057:Apolipoproteins E / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D012367:RNA, Viral / Q000032:analysis; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013223:Statistics as Topic; D014771:Virion / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D012367:RNA, Viral; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Apolipoprotein A1; Apolipoprotein E; HCV lipoviral particles; HDL-C; Low-density lipoprotein receptor; PCSK9