Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent.
OBJECTIVE
Maintenance of cholesterol homeostasis in human macrophages is essential to prevent foam cell formation. We evaluated the relative contribution of the ABCA1 and ABCG1 transporters to cholesterol efflux from human macrophages, and of the capacity of LXR agonists to reduce foam cell formation by stimulating export of cellular cholesterol.


RESULTS
ABCG1 mRNA levels were strongly increased in acLDL-loaded THP-1 macrophages and in HMDM on stimulation with LXR agonists. However, silencing of ABCG1 expression using ABCG1-specific siRNA indicated that ABCG1 was not essential for cholesterol efflux to HDL in cholesterol-loaded human macrophages stimulated with LXR agonists. Indeed, ABCA1 was solely responsible for the stimulation of cholesterol efflux to HDL on LXR activation, as this effect was abolished in HMDM from Tangier patients. Furthermore, depletion of cellular ATP indicated that the LXR-induced export of cholesterol was an ATP-dependent transport mechanism in human macrophages. Finally, use of an anti-Cla-1 blocking antibody identified the Cla-1 receptor as a key component in cholesterol efflux to HDL from cholesterol-loaded human macrophages.


CONCLUSIONS
Our data indicate that stimulation of cholesterol efflux to HDL by LXR agonists in human foam cells involves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression.
Larrede
Sandra
S
INSERM UMR S939, Paris, France.
Quinn
Carmel M
CM
Jessup
Wendy
W
Frisdal
Eric
E
Olivier
Maryline
M
Hsieh
Victar
V
Kim
Mi-Jurng
MJ
Van Eck
Miranda
M
Couvert
Philippe
P
Carrie
Alain
A
Giral
Philippe
P
Chapman
M John
MJ
Guerin
Maryse
M
Le Goff
Wilfried
W
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors*; D011336:Probability
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol