Combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages and distinct atherosclerosis at relatively low plasma cholesterol levels.
OBJECTIVE
The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis.


RESULTS
LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156+/-19x10(3) microm2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226+/-30x10(3) microm2; P<0.05) and not significantly different from single ABCG1 KO (117+/-22x10(3) microm2) and WT transplanted mice (112+/-15x10(3) microm2).


CONCLUSIONS
Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.
Out
Ruud
R
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands. r.out@lacdr.leidenuniv.nl
Hoekstra
Menno
M
Habets
Kim
K
Meurs
Illiana
I
de Waard
Vivian
V
Hildebrand
Reeni B
RB
Wang
Yanan
Y
Chimini
Giovanna
G
Kuiper
Johan
J
Van Berkel
Theo J C
TJ
Van Eck
Miranda
M
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000503:physiopathology*; D007958:Leukocyte Count; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency; D013154:Spleen / Q000473:pathology
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol