title: Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome.
abstract: To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 ± 9 mg/dl), low apoA-I (79 ± 24 mg/dl), normal LDL-cholesterol (132 ± 25 mg/dl), and elevated TG (130 ± 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to -25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to -48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rached
authors.affiliation: Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Camont
authors.affiliation: Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marcio H
authors.initials: MH
authors.lastname: Miname
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lhomme
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: Carolane
authors.initials: C
authors.lastname: Dauteuille
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: Sora
authors.initials: S
authors.lastname: Lecocq
authors.affiliation: Heart Institute-InCor, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Carlos V
authors.initials: CV
authors.lastname: Serrano
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, University of Pierre and Marie Curie - Paris 6, Pitié - Salpétrière University Hospital, ICAN, Paris, France.
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053305:Apolipoprotein C-III / Q000097:blood* / Q000378:metabolism; D001938:Brazil; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood* / Q000378:metabolism; D002788:Cholesterol Esters / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D018389:Codon, Nonsense; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood* / Q000378:metabolism; D053440:Lipoproteins, HDL3 / Q000097:blood / Q000378:metabolism; D008297:Male; D010743:Phospholipids / Q000097:blood / Q000378:metabolism; D013107:Sphingolipids / Q000097:blood / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D018389:Codon, Nonsense; D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D010743:Phospholipids; D013107:Sphingolipids; D014280:Triglycerides
keywords: HDL functionality; antioxidative activity; apolipoprotein A-I; cellular cholesterol efflux; familial deficiency; genetics; high density lipoprotein; lipidomics