Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues.
The ATP-binding cassette transporter 1 (ABCA1) has recently been identified as a key regulator of high-density lipoprotein (HDL) metabolism, which is defective in familial HDL-deficiency syndromes such as Tangier disease. ABCA1 functions as a facilitator of cellular cholesterol and phospholipid efflux, and its expression is induced during cholesterol uptake in macrophages. To assess the role of macrophage ABCA1 in atherosclerosis, we generated low-density lipoprotein (LDL) receptor knockout (LDLr(-/-)) mice that are selectively deficient in leukocyte ABCA1 (ABCA1(-/-)) by using bone marrow transfer (ABCA1(-/-) --> LDLr(-/-)). Here we demonstrate that ABCA1(-/-) --> LDLr(-/-) chimeras develop significantly larger and more advanced atherosclerotic lesions compared with chimeric LDLr(-/-) mice with functional ABCA1 in hematopoietic cells. Targeted disruption of leukocyte ABCA1 function did not affect plasma HDL cholesterol levels. The amount of macrophages in liver and spleen and peripheral blood leukocyte counts is increased in the ABCA1(-/-) --> LDLr(-/-) chimeras. Our results provide evidence that leukocyte ABCA1 plays a critical role in the protection against atherosclerosis, and we identify ABCA1 as a leukocyte factor that controls the recruitment of inflammatory cells.
van Eck
Miranda
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA Leiden, The Netherlands. M.Eck@LACDR.LeidenUniv.nl
Bos
I Sophie T
IS
Kaminski
Wolfgang E
WE
Orsó
Evelyn
E
Rothe
Gregor
G
Twisk
Jaap
J
Böttcher
Alfred
A
Van Amersfoort
Edwin S
ES
Christiansen-Weber
Trudy A
TA
Fung-Leung
Wai-Ping
WP
Van Berkel
Theo J C
TJ
Schmitz
Gerd
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001053:Apolipoproteins / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells; D002784:Cholesterol / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007962:Leukocytes / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001053:Apolipoproteins; D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol