ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis.
ABCA12 is involved in the transport of ceramides in skin, but it may play a wider role in lipid metabolism. We show that, in Abca12-deficient macrophages, cholesterol efflux failed to respond to activation with LXR agonists. Abca12 deficiency caused a reduction in the abundance of Abca1, Abcg1, and Lxrβ. Overexpression of Lxrβ reversed the effects. Mechanistically, Abca12 deficiency did not affect expression of genes involved in cholesterol metabolism. Instead, a physical association between Abca1, Abca12, and Lxrβ proteins was established. Abca12 deficiency enhanced interaction between Abca1 and Lxrβ and the degradation of Abca1. Overexpression of ABCA12 in HeLa-ABCA1 cells increased the abundance and stability of ABCA1. Abca12 deficiency caused an accumulation of cholesterol in macrophages and the formation of foam cells, impaired reverse cholesterol transport in vivo, and increased the development of atherosclerosis in irradiated Apoe(-/-) mice reconstituted with Apoe(-/-)Abca12(-/-) bone marrow. Thus, ABCA12 regulates the cellular cholesterol metabolism via an LXRβ-dependent posttranscriptional mechanism.
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Ying
Y
Fu
Nigora
N
Mukhamedova
Sally
S
Ip
Wilissa
W
D'Souza
Katya J
KJ
Henley
Tia
T
DiTommaso
Rajitha
R
Kesani
Michael
M
Ditiatkovski
Lynelle
L
Jones
Rachael M
RM
Lane
Garry
G
Jennings
Ian M
IM
Smyth
Benjamin T
BT
Kile
Dmitri
D
Sviridov
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000378:metabolism*
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C532573:Abca12 protein, mouse