Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels.
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.
Haghpassand
M
M
Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Bourassa
P A
PA
Francone
O L
OL
Aiello
R J
RJ
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
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL