Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

Article Article scientifique Article Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation eng 2019-11-21 2019-11-21 author Pagano Sabrina 0000-0001-7075-1182 758239 author Magenta Alessandra 0000-0002-9054-337X author D'Agostino Marco author Martino Francesco author Barillà Francesco author Satta Poschung Nathalie 134524 author Frias Miguel 0000-0001-6884-4793 502571 author Ronca Annalisa 0000-0002-9911-693X 967158 author Mach François 27365 author Gencer Baris 666056 author Favari Elda 0000-0002-5901-2482 author Vuilleumier Nicolas 61406 2035 10.3390/jcm8122035 31766415 2077-0383 PMC6947407 https://www.mdpi.com/2077-0383/8/12/2035 Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD). Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model. Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition. Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages. TLR2/4 Anti-apolipoprotein A-1 IgG Cholesterol homeostasis Familial hypercholesterolemia Foam cells MiR-33a Passive diffusion Dewey 616 Fondation Leenaards 3698 Swiss National Science Foundation Human autoantibody response to the C-terminal helix of apolipoprotein A-1 as new rationale for prognosis and treatment of cardiovascular disease 163335 CH Project funding De Reuter Foundation 315112 56 Département de médecine 221 false 211 Auto-immunité, inflammation et athérosclérose 270 325 Athérosclérose 591 Journal of clinical medicine 8 12 c0663493-fc98-4321-afab-14863ca9c90c Article (Published version) Public Article-scientifique-from-unpaywall.pdf 3715601 application/pdf CC BY-4.0 7d783fba-9d43-4640-b74d-a3406ee087e3 Appendix Public jcm-08-02035-s001.pdf 468920 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation	Journal of clinical medicine			2019	244	216

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Ronca, Annalisa