Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis.
OBJECTIVE
The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial.


RESULTS
We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr(-/-) background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe(-/-) background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr(-/-) background displayed no change in atherosclerotic lesion area.


CONCLUSIONS
These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis.
Brunham
Liam R
LR
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Singaraja
Roshni R
RR
Duong
MyNgan
M
Timmins
Jenelle M
JM
Fievet
Catherine
C
Bissada
Nagat
N
Kang
Martin H
MH
Samra
Amrit
A
Fruchart
Jean-Charles
JC
McManus
Bruce
B
Staels
Bart
B
Parks
John S
JS
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D011973:Receptors, LDL