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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial
Maryam Darabi1, Marie Lhomme2, Maharajah Ponnaiah3
1Sorbonne Université, INSERM (Drs Darabi, Guillas, Frisdal, Poupel, Carrie,Bittar, Guerin, Le Goff, and Kontush), Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, F-75013 Paris, France; LPS-BioSciences (Current affiliation of Dr Darabi), Université de Paris-Saclay, Orsay, France.
Insights
Gain-of-function PCSK9 variants impair high-density lipoprotein (HDL) functionality and alter its composition, contributing to cardiovascular risk. This study reveals novel insights into HDL
Area of Science:
- Cardiovascular Biology
- Lipid Metabolism
- Proteomics and Glycomics
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in dyslipidemia beyond LDL receptor activity.
- PCSK9's impact on high-density lipoprotein (HDL) physiology may influence cardiovascular risk.
Purpose of the Study:
- To assess PCSK9-driven alterations in HDL physiology.
- To investigate the contribution of these alterations to the cardiovascular risk profile.
Main Methods:
- HDL was isolated from patients with familial hypercholesterolemia (FH) with PCSK9 gain-of-function (FH-PCSK9), FH with LDL-R variants (treated and untreated), and normolipidemic controls.
- Functional, proteomic, lipidomic, and glycomic analyses were performed on HDL.
- A novel mosaic structure-function model of HDL biology was developed using network analysis.
Main Results:
- FH-PCSK9 patients exhibited multiple HDL functional deficiencies, including reduced antioxidative, antiapoptotic, anti-thrombotic, and anti-inflammatory activities.
- HDL cellular cholesterol efflux capacity remained unchanged in FH-PCSK9 patients.
- Distinct alterations in HDL proteomic, lipidomic, and glycomic composition were observed, with enrichment in lysophospholipids, A2G2S2 glycan, and apolipoprotein A-IV.
Conclusions:
- Anti-atherogenic HDL functionalities are altered in FH-PCSK9 patients, accompanied by specific compositional changes.
- This study provides the first comprehensive overview of how gain-of-function PCSK9 genetic variants affect HDL structure-function relationships.
Background:
The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity.
Objective:
This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile.
Methods:
HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls. Biological evaluations paralleled by proteomic, lipidomic and glycomic analyses were applied to characterize functional and compositional properties of HDL.
Results:
Multiple deficiencies in the HDL function were identified in the FH-PCSK9 group relative to dyslipidemic FH-LDLR patients and normolipidemic controls, which involved reduced antioxidative, antiapoptotic, anti-thrombotic and anti-inflammatory activities. By contrast, cellular cholesterol efflux capacity of HDL was unchanged. In addition, multiple alterations of the proteomic, lipidomic and glycomic composition of HDL were found in the FH-PCSK9 group. Remarkably, HDLs from FH-PCSK9 patients were systematically enriched in several lysophospholipids as well as in A2G2S2 (GP13) glycan and apolipoprotein A-IV. Based on network analysis of functional and compositional data, a novel mosaic structure-function model of HDL biology involving FH was developed.
Conclusion:
Several metrics of anti-atherogenic HDL functionality are altered in FH-PCSK9 patients paralleled by distinct compositional alterations. These data provide a first-ever overview of the impact of GOF PCSK9 genetic variants on structure-function relationships in HDL.
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