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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Circulating PCSK9 levels and CETP plasma activity are independently associated in patients with metabolic diseases
Josefa Girona1,2, Daiana Ibarretxe1,2, Nuria Plana1,2
1Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, IISPV, C Sant Llorenç, 21, 43201, Reus, Spain.
Background:
PCSK9 inhibition is a new powerful cholesterol-lowering strategy. Recently, it was reported that CETP inhibitors influence PCSK9 levels as an off-target effect. We explored the relationship between circulating PCSK9 levels and CETP activity in patients with metabolic disease who were not on lipid-lowering therapy.
Methods:
Plasma CETP activity and PCSK9 levels were measured in 450 participants (median age, 58 years; 49 % women) who attended the metabolism unit because of metabolic syndrome (MetS) (78 %), atherogenic dyslipidemia (32 %), obesity (50 %), type 2 diabetes mellitus (72 %), and other risk factors (13 %). A 6 week lipid-lowering drug wash-out period was established in treated patients.
Results:
Both PCSK9 levels and CETP activity were higher in patients with an increasing number of MetS components. PCSK9 levels were positively correlated with CETP activity in the entire cohort (r = 0.256, P < 0.0001) independent of age, gender, body mass index (BMI), systolic blood pressure (SBP), LDL cholesterol (LDL-C), triglycerides and glucose. Individuals with the loss-of-function PCSK9 genetic variant rs11591147 (R46L) had lower levels of PCSK9 (36.5 %, P < 0.0001) and LDL-C (17.8 %, P = 0.010) as well as lower CETP activity (10.31 %, P = 0.009). This association remained significant in the multiple regression analysis even after adjusting for gender, age, BMI, LDL-C, triglycerides, glucose, lecithin-cholesterol acyltransferase, SBP and MetS (P = 0.003).
Conclusions:
Our data suggest a metabolic association between PCSK9 and CETP independent of lipid-lowering treatment. The clinical implications of this metabolic relationship could be relevant for explaining the effect of PCSK9 and CETP inhibition on overall lipid profiles.
Insights
Cholesterollowering strategies PCSK9 and CETP show a metabolic link in patients with metabolic disease. This association between PCSK9 and CETP activity is independent of lipid-lowering treatments.
Area of Science:
- Metabolic disease research
- Cardiovascular risk factors
- Lipid metabolism
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potent cholesterol-lowering therapy.
- Cholesteryl ester transfer protein (CETP) inhibitors may influence PCSK9 levels as an off-target effect.
- The relationship between PCSK9 and CETP activity in patients with metabolic disease requires further investigation.
Purpose of the Study:
- To explore the relationship between circulating PCSK9 levels and CETP activity.
- To investigate this relationship in patients with metabolic diseases not receiving lipid-lowering therapy.
Main Methods:
- Plasma CETP activity and PCSK9 levels were measured in 450 participants with metabolic syndrome, dyslipidemia, obesity, or type 2 diabetes.
- A 6-week lipid-lowering drug wash-out period was implemented for treated patients.
- Genetic analysis included the PCSK9 loss-of-function variant rs11591147 (R46L).
Main Results:
- PCSK9 levels and CETP activity increased with the number of metabolic syndrome components.
- A significant positive correlation was found between PCSK9 levels and CETP activity (r=0.256, P<0.0001), independent of various clinical factors.
- Individuals with the PCSK9 R46L variant exhibited lower PCSK9, LDL-C, and CETP activity.
Conclusions:
- A metabolic association exists between PCSK9 and CETP, independent of lipid-lowering treatments.
- This relationship may help explain the effects of PCSK9 and CETP inhibition on lipid profiles.
- Further research into this metabolic link could inform therapeutic strategies for cardiovascular disease.
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