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

Abstract

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...

Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

“…Moreover, inhibition of PCSK9 expression resulted in a two-fold increase in hepatic LDL receptor levels [Graham et al, 2007]. These experiments confirmed that inhibition of PCSK9 activity should enhance statin hypocholesterolemic effect by increasing LDL receptor number [Rashid et al, 2005;Careskey et al, 2008]. Finally, the low plasma LDL-C levels and the reduction of CHD displayed in PCSK9 loss-of-function mutation carriers, which seem furthermore healthy, indicate that the inhibition of PCSK9 should be an effective target in the treatment of hypercholesterolemia with no known adverse side effects.…”

“…Serum PCSK9 measured by ELISA seems directly correlated with serum LDL-C and total cholesterol [Alborn et al, 2007]. Atorvastatin (40 mg/ day) increases human serum levels of PCSK9 by 34% compared with baseline and placebo [Careskey et al, 2008], while fenofibrate (200 mg/day) decreased plasma PCSK9 concentrations by 8.5% in diabetic patients [Lambert et al, 2008]. However, a standardized method, with specific antibodies, is still needed to compare the levels of PCSK9 measured in different studies.…”

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

“…Statins have been known to increase the nuclear translocation of sterol-regulatory element binding protein-2 (SREBP-2), which activates not only the LDLR but also PCSK9 gene expression [4][5][6]. Subsequently, statins increases serum PCSK9 levels [5][6][7][8] and this increment may attenuate the LDL-C lowering effect of statins. It may in a part explain the rule of 6% for statins, which indicates that each doubling of the statin dose results in only about a 6% further decrease in LDL-C.…”

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

“…Statins increase PCSK9 levels [16], which probably accounts, in large part, for the limits in the incremental effectiveness of statins during up-titration [17]. Because of the intersecting mechanisms of statins enhancing LDL receptor (LDL-R) activity and lowering LDL-C, but also increasing PCSK9 expression (which can in turn destroy LDL-Rs and reduce LDL-C lowering effects), the combination of statins and PCSK9 inhibitors could theoretically have positive complementary and additive effects on LDL-C reduction [18].…”