title: Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels.
abstract: Excess accumulation of cholesterol in macrophages results in foam cell production and lesion development. Recent studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) is highly regulated in macrophages and mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for HDL formation. The goal of this study was to determine the contribution of monocyte/macrophage ABCA1 to HDL formation in vivo. We generated mice expressing ABCA1 in macrophages and mice with selected inactivation of ABCA1 in macrophages by bone marrow transplantation in ABCA1-deficient (ABC1(-/-)) and wild-type (WT) mice. At all times, the level of HDL in ABC1(-/-) recipient mice remained low relative to WT recipient mice irrespective of the genotype of the donor macrophage ABCA1 or high-fat feeding. Expression of WT macrophage ABCA1 in ABC1(-/-) mice resulted in a small but significant increase in apoA-I levels starting 2 weeks after transplantation. No further increase in apoAI was observed up to 14 weeks after transplantation. The increase in apoAI was accompanied by a small but significant increase in HDL cholesterol 6 weeks after transplantation. The HDL formed as a consequence of the expression of WT macrophage ABCA1 migrated to the alpha position in a two-dimensional gel electrophoresis. These results demonstrate that monocyte/macrophage ABCA1 contributes to HDL formation; however, the contribution to the overall plasma HDL levels is minimal.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
authors.forename: M
authors.initials: M
authors.lastname: Haghpassand
authors.forename: P A
authors.initials: PA
authors.lastname: Bourassa
authors.forename: O L
authors.initials: OL
authors.lastname: Francone
authors.forename: R J
authors.initials: RJ
authors.lastname: Aiello
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016026:Bone Marrow Transplantation; D003433:Crosses, Genetic; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D011485:Protein Binding; D013631:Tangier Disease; D013997:Time Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL