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Journal of Lipid Research, Vol. 49, 394-398, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9

Holly E. Careskey, R. Aleks Davis, William E. Alborn, Jason S. Troutt, Guoqing Cao and Robert J. Konrad¹

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285

Published, JLR Papers in Press, November 21, 2007.

¹ To whom correspondence should be addressed. e-mail: konrad_robert{at}lilly.com

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has gained attention as a key regulator of serum low density lipoprotein cholesterol (LDL-C) levels. This novel protease causes the degradation of hepatic low density lipoprotein receptors. In humans, gain-of-function mutations in PCSK9 cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDL-C levels and cardiovascular risk. Previous studies have demonstrated that statins upregulate PCSK9 mRNA expression in cultured cells and animal models. In light of these observations, we studied the effect of atorvastatin on circulating PCSK9 protein levels in humans using a sandwich ELISA to quantitate serum PCSK9 levels in patients treated with atorvastatin or placebo for 16 weeks. We observed that atorvastatin (40 mg/day) significantly increased circulating PCSK9 levels by 34% compared with baseline and placebo and decreased LDL-C levels by 42%. These results suggest that the addition of a PCSK9 inhibitor to statin therapy may result in even further LDL-C decreases.

Supplementary key words low density lipoprotein • low density lipoprotein cholesterol • low density lipoprotein receptor

Abbreviations: apoB, apolipoprotein B; LDL-C, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SREBP-2, sterol-regulatory element binding protein-2

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