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. The serum protease proprotein convertase subtilisin/ kexin type 9 (PCSK9) has gained tremendous attention as a potential key regulator of serum low density lipoprotein cholesterol (LDL-C) levels (1-3). PCSK9 is a protease made by the liver that acts to degrade hepatic low density lipoprotein receptors (LDLRs) (4-10). The mechanism by which PCSK9 degrades LDLRs is extremely complex and is only beginning to be understood. It was recently suggested that the protease itself does not have to be proteolytically active to cause degradation of the LDLR but rather binds to the LDLR and subsequently targets it for intracellular destruction within the hepatocyte (11-13). Regardless of the exact mechanism, the result of LDLR levels being decreased is that the liver has a decreased ability to bind LDL from the circulation and serum LDL-C levels increase. Therefore, mutations in PCSK9 can have dramatic effects on serum LDL-C levels in humans.Patients with gain-of-function mutations of PCSK9 manifest severe familial hypercholesterolemia and accompanying increased cardiovascular risk (14-17). These mutations in PCSK9 account for ?10-25% of familial dominant hypercholesterolemia cases that could not be explained by mutations in either the LDLR or apolipoprotein B (apoB) (14-17). In contrast, heterozygous subjects with loss-of-function mutations in PCSK9, including mutations that prevent the self-cleavage and secretion of the protein itself, have significantly decreased levels of serum LDL-C and dramatically decreased cardiovascular risk (18)(19)(20). Approximately 2% of African-Americans carry such mutations, with an accompanying 80-90% decreased risk of serious cardiovascular events (18). Recently, the first compound heterozygote for PCSK9 loss-of-function mutations was described. This subject, a healthy 32 year old female, had an extremely low serum LDL-C level of 14 mg/dl (20).Interestingly, statins have been shown to increase the activity/nuclear t...
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 g/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.
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