title: Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages.
abstract: The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice and LDLR receptor-deficient (LDLr(-/-)) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE(-/-) and LDLr(-/-) mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr(-/-) or the apoE(-/-) mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE(-/-). Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut, USA. Robert_J_Aiello@groton.pfizer.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Aiello
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.forename: Patricia-Ann
authors.initials: PA
authors.lastname: Bourassa
authors.forename: Lori
authors.initials: L
authors.lastname: Royer
authors.forename: Saralyn
authors.initials: S
authors.lastname: Lindsey
authors.forename: Timothy
authors.initials: T
authors.lastname: Coskran
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Haghpassand
authors.forename: Omar L
authors.initials: OL
authors.lastname: Francone
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood*; D003433:Crosses, Genetic; D005260:Female; D006949:Hyperlipidemias / Q000150:complications* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008811:Mice, Inbred DBA / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency*; D014973:Xanthomatosis / Q000473:pathology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol