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Received on October 30, 2007
Accepted on March 25, 2008
Lipids, Lipoproteins, and Cardiovascular Risk Factors |
1 The Heart Research Institute, Sydney, Australia, and Université de Nantes, INSERM U539, Nantes, France
2 GlaxoSmithkline, CVU CEDD, Les Ulis, France
3 The Heart Research Institute, Sydney, Australia
4 the Royal Prince Alfred Hospital, Sydney, Australia
5 The Heart Research Institute, Sydney, Australia, and The University of Sydney, Sydney, Australia
* To whom correspondence should be addressed. E-mail: lambertg{at}hri.org.au.
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment.
METHODS: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment.
RESULTS: We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048).
CONCLUSIONS: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol–lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.
The following articles in journals at HighWire Press have cited this article:
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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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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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 D. L. Rainwater, L. A. Cox, J. Rogers, J. L. VandeBerg, and M. C. Mahaney Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons J. Lipid Res., July 1, 2009; 50(7): 1420 - 1428. [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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 M. C. McNutt, H. J. Kwon, C. Chen, J. R. Chen, J. D. Horton, and T. A. Lagace Antagonism of Secreted PCSK9 Increases Low Density Lipoprotein Receptor Expression in HepG2 Cells J. Biol. Chem., April 17, 2009; 284(16): 10561 - 10570. [Abstract] [Full Text] [PDF]
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J. D. Horton, J. C. Cohen, and H. H. Hobbs PCSK9: a convertase that coordinates LDL catabolism J. Lipid Res., April 1, 2009; 50(Supplement): S172 - S177. [Abstract] [Full Text] [PDF]
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