Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia - Institut de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition Access content directly
Journal Articles Journal of clinical lipidology Year : 2023

Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia

Marie Lhomme
  • Function : Author
Maharajah Ponnaiah
  • Function : Author
Maja Pučić-Baković
  • Function : Author
Isabelle Guillas
Eric Frisdal
  • Function : Author
Randa Bittar
  • Function : Author
Mikaël Croyal
Lucrèce Matheron-Duriez
  • Function : Author
Lucie Poupel
  • Function : Author
Dominique Bonnefont-Rousselot
Corinne Frere
  • Function : Author
Mathilde Varret
  • Function : Author
Michel Krempf
  • Function : Author
Bertrand Cariou
  • Function : Author
Gordan Lauc
  • Function : Author
Maryse Guerin
Alain Carrie
  • Function : Author
Eric Bruckert
  • Function : Author
Philippe Giral
Wilfried Le Goff
  • Function : Author
Anatol Kontush

Abstract

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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Dates and versions

hal-04192389 , version 1 (06-09-2023)

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Maryam Darabi, Marie Lhomme, Maharajah Ponnaiah, Maja Pučić-Baković, Isabelle Guillas, et al.. Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia. Journal of clinical lipidology, 2023, ⟨10.1016/j.jacl.2023.07.003⟩. ⟨hal-04192389⟩
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