Cellular cholesterol efflux in heterozygotes for tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size
| Autor: | M E, Brousseau, G P, Eberhart, J, Dupuis, B F, Asztalos, A L, Goldkamp, E J, Schaefer, M W, Freeman |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Heterozygote Apolipoprotein A-I Cholesterol HDL Biological Transport Fibroblasts Middle Aged Lipids Pedigree Cohort Studies Haplotypes Humans ATP-Binding Cassette Transporters Electrophoresis Gel Two-Dimensional Female Particle Size Lipoproteins HDL Tangier Disease ATP Binding Cassette Transporter 1 Aged Glycoproteins |
| Zdroj: | Journal of lipid research. 41(7) |
| ISSN: | 0022-2275 |
| Popis: | 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 (P0.000) 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 (P0.000) 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, P0. 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. |
| Databáze: | OpenAIRE |
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