scholarly journals Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia

2011 ◽  
Vol 121 (9) ◽  
pp. 397-403 ◽  
Author(s):  
Martijn C.G.J. Brouwers ◽  
Marleen M.J. van Greevenbroek ◽  
Jason S. Troutt ◽  
Angela Bonner Freeman ◽  
Ake Lu ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Significant Rise ◽  
Low Density ◽  
Proprotein Convertase ◽  
Once Daily ◽  
Heritable Trait ◽  
The Relationship

The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)–apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)–apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67–84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.

scholarly journals Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

2019 ◽  
Vol 115 (3) ◽  
pp. 510-518 ◽  
Author(s):  
Nabil G Seidah ◽  
Annik Prat ◽  
Angela Pirillo ◽  
Alberico Luigi Catapano ◽  
Giuseppe Danilo Norata
Keyword(s):  
Monoclonal Antibodies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Loss Of Function ◽  
Proprotein Convertase ◽  
Innovative Strategies ◽  
Density Lipoprotein Receptor ◽  
Low Levels

Abstract Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2–4 weeks, they trigger a ∼60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in ∼50–60% LDL-C lowering that lasts up to 6 months (Phases II–III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.

scholarly journals Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 134 ◽  
Author(s):  
Michael D. Shapiro ◽  
Sergio Fazio
Keyword(s):  
Cardiovascular Disease ◽  
Apolipoprotein B ◽  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density Lipoproteins ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Lines Of Evidence

Cholesterol-rich, apolipoprotein B (apoB)-containing lipoproteins are now widely accepted as the most important causal agents of atherosclerotic cardiovascular disease. Multiple unequivocal and orthogonal lines of evidence all converge on low-density lipoprotein and related particles as being the principal actors in the genesis of atherosclerosis. Here, we review the fundamental role of atherogenic apoB-containing lipoproteins in cardiovascular disease and several other humoral and parietal factors that are required to initiate and maintain arterial degeneration. The biology of foam cells and their interactions with high-density lipoproteins, including cholesterol efflux, are also briefly reviewed.

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