Homozygous carriers of the apolipoprotein ε2 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein ε2 (ε2/ε2; n=12), normal controls (n=72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n=38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in ε2/ε2 and FCHL patients. Median circulating PCSK9 levels did not differ between ε2/ε2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P=0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in ε2/ε2 carriers (P<0.05). These associations were stronger in ε2/ε2 carriers when compared with controls (P values for interaction=0.01 and 0.02 respectively). A direct comparison with FCHL patients demonstrated a similar discrepancy for the association with plasma triacylglycerols and also VLDL-apolipoprotein B, cholesterol and triacylglycerols (P value for interaction=0.01, 0.01, 0.03 and 0.03 respectively). Plasma PCSK9 is associated with type III hyperlipidaemia. Its strong relationship with plasma triacylglycerols and total cholesterol distinguishes ε2/ε2 carriers from controls and another type of dyslipidaemia, which provides valuable information regarding the pathogenesis of this complex dyslipidaemia. Furthermore, these results suggest that patients with type III hyperlipidaemia may benefit from PCSK9-antagonizing therapy.
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Research Article|
January 22 2014
Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2
Martijn C. G. J. Brouwers;
*Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands
Correspondence: Mr Martijn C.G.J. Brouwers (email martijn.brouwers@maastrichtuniversity.nl).
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Marleen M. J. van Greevenbroek;
Marleen M. J. van Greevenbroek
*Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands
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Robert J. Konrad;
Robert J. Konrad
†Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IA 46285, U.S.A.
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Jason S. Troutt;
Jason S. Troutt
†Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IA 46285, U.S.A.
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Nicolaas C. Schaper;
Nicolaas C. Schaper
*Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands
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Coen D. A. Stehouwer
Coen D. A. Stehouwer
*Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maasctricht, The Netherlands
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Publisher: Portland Press Ltd
Received:
September 05 2013
Revision Received:
November 19 2013
Accepted:
December 06 2013
Accepted Manuscript online:
December 06 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (9): 679–684.
Article history
Received:
September 05 2013
Revision Received:
November 19 2013
Accepted:
December 06 2013
Accepted Manuscript online:
December 06 2013
Citation
Martijn C. G. J. Brouwers, Marleen M. J. van Greevenbroek, Robert J. Konrad, Jason S. Troutt, Nicolaas C. Schaper, Coen D. A. Stehouwer; Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2. Clin Sci (Lond) 1 May 2014; 126 (9): 679–684. doi: https://doi.org/10.1042/CS20130556
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