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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
aAddress correspondence to this author at: Eli Lilly and Company, Indianapolis, IN 46285. Fax: 317-276-5281; e-mail konrad_robert{at}lilly.com.
Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum.
Methods: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation.
Results: Serum concentrations of PCSK9 ranged from 11 to 115 µg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL.
Conclusions: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.
The following articles in journals at HighWire Press have cited this article:
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  J. S. Troutt, W. E. Alborn, G. Cao, and R. J. Konrad Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels J. Lipid Res., February 1, 2010; 51(2): 345 - 351. [Abstract] [Full Text] [PDF]
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G. Dubuc, M. Tremblay, G. Pare, H. Jacques, J. Hamelin, S. Benjannet, L. Boulet, J. Genest, L. Bernier, N. G. Seidah, et al. A new method for measurement of total plasma PCSK9: clinical applications J. Lipid Res., January 1, 2010; 51(1): 140 - 149. [Abstract] [Full Text] [PDF]
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 B. Cariou, K. Ouguerram, Y. Zair, R. Guerois, C. Langhi, S. Kourimate, I. Benoit, C. Le May, C. Gayet, K. Belabbas, et al. PCSK9 Dominant Negative Mutant Results in Increased LDL Catabolic Rate and Familial Hypobetalipoproteinemia Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2191 - 2197. [Abstract] [Full Text] [PDF]
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 S. E. Humphries, R. D. G. Neely, R. A. Whittall, J. S. Troutt, R. J. Konrad, M. Scartezini, K. W. Li, J. A. Cooper, J. Acharya, and A. Neil Healthy Individuals Carrying the PCSK9 p.R46L Variant and Familial Hypercholesterolemia Patients Carrying PCSK9 p.D374Y Exhibit Lower Plasma Concentrations of PCSK9 Clin. Chem., December 1, 2009; 55(12): 2153 - 2161. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. Lambert, P. H. R. Barrett, K.-A. Rye, E. M.M. Ooi, and G. F. Watts Plasma Proprotein Convertase Subtilisin/Kexin Type 9: A Marker of LDL Apolipoprotein B-100 Catabolism? Clin. Chem., November 1, 2009; 55(11): 2049 - 2052. [Abstract] [Full Text] [PDF]
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 S. Poirier, G. Mayer, V. Poupon, P. S. McPherson, R. Desjardins, K. Ly, M.-C. Asselin, R. Day, F. J. Duclos, M. Witmer, et al. Dissection of the Endogenous Cellular Pathways of PCSK9-induced Low Density Lipoprotein Receptor Degradation: EVIDENCE FOR AN INTRACELLULAR ROUTE J. Biol. Chem., October 16, 2009; 284(42): 28856 - 28864. [Abstract] [Full Text] [PDF]
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A. Baass, G. Dubuc, M. Tremblay, E. E. Delvin, J. O'Loughlin, E. Levy, J. Davignon, and M. Lambert Plasma PCSK9 Is Associated with Age, Sex, and Multiple Metabolic Markers in a Population-Based Sample of Children and Adolescents Clin. Chem., September 1, 2009; 55(9): 1637 - 1645. [Abstract] [Full Text] [PDF]
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 S. G. Lakoski, T. A. Lagace, J. C. Cohen, J. D. Horton, and H. H. Hobbs Genetic and Metabolic Determinants of Plasma PCSK9 Levels J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2537 - 2543. [Abstract] [Full Text] [PDF]
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S. Blesa, S. Vernia, A.-B. Garcia-Garcia, S. Martinez-Hervas, C. Ivorra, V. Gonzalez-Albert, J. F. Ascaso, J. C. Martin-Escudero, J. T. Real, R. Carmena, et al. A New PCSK9 Gene Promoter Variant Affects Gene Expression and Causes Autosomal Dominant Hypercholesterolemia J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3577 - 3583. [Abstract] [Full Text] [PDF]
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A. S. Peterson, L. G. Fong, and S. G. Young Errata. PCSK9 function and physiology J. Lipid Res., July 1, 2008; 49(7): 1595 - 1599. [Abstract] [Full Text] [PDF]
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A. Grefhorst, M. C. McNutt, T. A. Lagace, and J. D. Horton Plasma PCSK9 preferentially reduces liver LDL receptors in mice J. Lipid Res., June 1, 2008; 49(6): 1303 - 1311. [Abstract] [Full Text] [PDF]
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A. S. Peterson, L. G. Fong, and S. G. Young PCSK9 function and physiology J. Lipid Res., June 1, 2008; 49(6): 1152 - 1156. [Full Text] [PDF]
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G. Lambert, N. Ancellin, F. Charlton, D. Comas, J. Pilot, A. Keech, S. Patel, D. R. Sullivan, J. S. Cohn, K.-A. Rye, et al. Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment Clin. Chem., June 1, 2008; 54(6): 1038 - 1045. [Abstract] [Full Text] [PDF]
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H. E. Careskey, R. A. Davis, W. E. Alborn, J. S. Troutt, G. Cao, and R. J. Konrad Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9 J. Lipid Res., February 1, 2008; 49(2): 394 - 398. [Abstract] [Full Text] [PDF]
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