Increased ABCA1 activity protects against atherosclerosis.
The ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC(+)) were crossed with ApoE(-/-) mice, a strain that spontaneously develop atherosclerotic lesions. BAC(+)ApoE(-/-) mice developed dramatically smaller, less-complex lesions as compared with their ApoE(-/-) counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC(+)ApoE(-/-) mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC(+)ApoE(-/-) mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC(+)ApoE(-/-) mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux.
Singaraja
Roshni R
RR
Centre for Molecular Medicine and Therapeutics, Children's and Women's Hospital, University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
Fievet
Catherine
C
Castro
Graciela
G
James
Erick R
ER
Hennuyer
Nathalie
N
Clee
Susanne M
SM
Bissada
Nagat
N
Choy
Jonathan C
JC
Fruchart
Jean-Charles
JC
McManus
Bruce M
BM
Staels
Bart
B
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D001054:Apolipoproteins A / Q000097:blood; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001693:Biological Transport, Active; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010743:Phospholipids / Q000097:blood; D014018:Tissue Distribution
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D010743:Phospholipids; C022205:apolipoprotein A-IV; D002784:Cholesterol