title: Cellular cholesterol efflux in heterozygotes for tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size.
abstract: Tangier disease (TD), caused by mutations in the ATP-binding cassette 1 (ABC-1) gene, is a rare genetic disorder characterized by severe deficiency of high density lipoproteins (HDL) in the plasma, hypercatabolism of HDL, and defective apolipoprotein (apo)-mediated cellular cholesterol efflux. In the present study, we assessed plasma lipid concentrations, HDL particle size and subspecies, and cellular cholesterol efflux in 9 TD heterozygotes from a kindred in which the proband was homozygous for an A-->C missense mutation at nucleotide 5338 of the ABC-1 transcript. Relative to age- and gender-matched controls from the Framingham Offspring Study (FOS), TD heterozygotes had significant reductions (P < 0.000) in HDL-C (-54% female; -40% male) and apoA-I (-33% female; -37% male) concentrations, as well as significantly less cholesterol (-68% female; -58% male) distributed in the largest HDL subclasses, H5 and H4. Consequently, HDL particle size (nm) was significantly smaller (P < 0.000) in TD heterozygotes (8.6 +/- 0.6 female; 8.7 +/- 0.1 male) relative to FOS controls (9.4 +/- 0.4 female; 9.0 +/- 0.3 male). Further studies demonstrated that apoA-I-mediated cellular cholesterol efflux in TD heterozygotes was essentially half that of controls (11 +/- 2 vs. 20 +/- 3% of total [(3)H]cholesterol, P < 0. 001), with strong correlations observed between cholesterol efflux and both HDL-C level (r = 0.600) and particle size (r = 0.680). In summary, our data demonstrate that apolipoprotein-mediated cholesterol efflux is aberrant in TD heterozygotes, as it is in homozygotes. This finding, along with the associations observed between HDL-C concentration, HDL particle size, and cholesterol efflux, supports the concept that plasma HDL-C levels are regulated, in part, by cholesterol efflux, which in turn influences HDL particle size and, ultimately, HDL apoA-I catabolism.
authors.affiliation: Lipid Metabolism Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: G P
authors.initials: GP
authors.lastname: Eberhart
authors.forename: J
authors.initials: J
authors.lastname: Dupuis
authors.forename: B F
authors.initials: BF
authors.lastname: Asztalos
authors.forename: A L
authors.initials: AL
authors.lastname: Goldkamp
authors.forename: E J
authors.initials: EJ
authors.lastname: Schaefer
authors.forename: M W
authors.initials: MW
authors.lastname: Freeman
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism*; D001692:Biological Transport; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D015331:Cohort Studies; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000145:classification; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D010375:Pedigree; D013631:Tangier Disease / Q000235:genetics*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D006023:Glycoproteins; D008055:Lipids; D008075:Lipoproteins, HDL