Macrophage ABCA5 deficiency influences cellular cholesterol efflux and increases susceptibility to atherosclerosis in female LDLr knockout mice.
OBJECTIVE
To determine the role of macrophage ATP-binding cassette transporter A5 (ABCA5) in cellular cholesterol homeostasis and atherosclerotic lesion development.


RESULTS
Chimeras with dysfunctional macrophage ABCA5 (ABCA5(-M/-M)) were generated by transplantation of bone marrow from ABCA5 knockout (ABCA5(-/-)) mice into irradiated LDLr(-/-) mice. In vitro, bone marrow-derived macrophages from ABCA5(-M/-M) chimeras exhibited a 29% (P<0.001) decrease in cholesterol efflux to HDL, whereas a 21% (P=0.07) increase in cholesterol efflux to apoA-I was observed. Interestingly, expression of ABCA1, but not ABCG1, was up-regulated in absence of functional ABCA5 in macrophages. To induce atherosclerosis, the transplanted LDLr(-/-) mice were fed a high-cholesterol Western-type diet (WTD) for 6, 10, or 18weeks, allowing analysis of effects on initial as well as advanced lesion development. Atherosclerosis development was not affected in male ABCA5(-M/-M) chimeras after 6, 10, and 18weeks WTD feeding. However, female ABCA5(-M/-M) chimeras did develop significantly (P<0.05) larger aortic root lesions as compared with female controls after 6 and 10weeks WTD feeding.


CONCLUSIONS
ABCA5 influences macrophage cholesterol efflux, and selective disruption of ABCA5 in macrophages leads to increased atherosclerotic lesion development in female LDLr(-/-) mice.
Ye
Dan
D
Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands. y.dan@lacdr.leidenuniv.nl
Meurs
Illiana
I
Ohigashi
Megumi
M
Calpe-Berdiel
Laura
L
Habets
Kim L L
KL
Zhao
Ying
Y
Kubo
Yoshiyuki
Y
Yamaguchi
Akihito
A
Van Berkel
Theo J C
TJ
Nishi
Tsuyoshi
T
Van Eck
Miranda
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics
C501079:ABCA5 protein, mouse; D018528:ATP-Binding Cassette Transporters; D008055:Lipids; D011973:Receptors, LDL; D002784:Cholesterol