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Open AccessArticle

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

1
Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
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Department of Internal Medicine Specialities, Medical Faculty, Geneva University, 1 rue Michel Servet, 1206 Geneva, Switzerland
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Fondazione Luigi Maria Monti, Istituto Dermopatico dell’ Immacolata-IRCCS, Experimental Immunology Laboratory, Via dei Monti di Creta 104, 00167 Rome, Italy
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Department of Pediatrics, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
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Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatrical Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
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Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
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Division of Cardiology, Geneva University Hospital, 1205 Geneva, Switzerland
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(12), 2035; https://doi.org/10.3390/jcm8122035
Received: 5 November 2019 / Accepted: 18 November 2019 / Published: 21 November 2019
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. View Full-Text
Keywords: anti-apolipoprotein A-1 IgG; familial hypercholesterolemia; cholesterol homeostasis; foam cells; miR-33a; TLR2/4; passive diffusion anti-apolipoprotein A-1 IgG; familial hypercholesterolemia; cholesterol homeostasis; foam cells; miR-33a; TLR2/4; passive diffusion
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Pagano, S.; Magenta, A.; D’Agostino, M.; Martino, F.; Barillà, F.; Satta, N.; Frias, M.A.; Ronca, A.; Mach, F.; Gencer, B.; Favari, E.; Vuilleumier, N. Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation. J. Clin. Med. 2019, 8, 2035.

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