Epoxycholesterol impairs cholesteryl ester hydrolysis in macrophage foam cells, resulting in decreased cholesterol efflux.
OBJECTIVE
Strategies to inhibit or reverse cholesterol accumulation in macrophages have been shown to be atheroprotective. Notably, the administration of LXR agonists upregulates key players in the reverse cholesterol transport pathway, including the ABCA1 and ABCG1 transporters. However, the effects of natural LXR activators, oxysterols, on lipid-laden macrophages remains elusive.


RESULTS
We assessed the ability of 2 oxysterols, 22(R)-hydroxycholesterol (22-OH) and 24(S),25-epoxycholesterol (epoxycholesterol), to promote cholesterol efflux to apoA-I from LDL- and modified LDL-labeled and loaded macrophages and thus rescue the phenotype associated with the accumulation of cellular cholesterol in these cells. In macrophages labeled with LDL-derived cholesterol, epoxycholesterol treatment enhances ABCA1-mediated cholesterol efflux. In contrast, in AcLDL-loaded macrophages, epoxycholesterol treatment decreases cholesterol efflux to apoA-I, despite a dramatic increase in the expression of ABCA1 in response to epoxycholesterol treatment. We show that the decreased efflux is attributable to impaired cholesterol mobilization from lipid droplets, resulting from decreased cholesteryl ester hydrolase activity.


CONCLUSIONS
Epoxycholesterol impairs cholesteryl ester hydrolysis activity in macrophage foam cells, thus reducing the availability of cholesterol for efflux to cholesterol acceptors.
Ouimet
Mireille
M
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario K1Y4W7, Canada.
Wang
Ming-Dong
MD
Cadotte
Natalie
N
Ho
Kenneth
K
Marcel
Yves L
YL
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000494:pharmacology; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D002787:Sterol Esterase / Q000378:metabolism*
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008078:Cholesterol, LDL; D006888:Hydroxycholesterols; D008074:Lipoproteins; C003585:22-hydroxycholesterol; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D002787:Sterol Esterase