Glucocorticoid receptor regulates ATP-binding cassette transporter-A1 expression and apolipoprotein-mediated cholesterol efflux from macrophages.
OBJECTIVE
The ATP-binding cassette transporter-A1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis. The objective of this study was to investigate the effect of dexamethasone (Dex) and other glucocorticoid receptor (GR) ligands on apolipoprotein AI-mediated cholesterol efflux from macrophages and ABCA1 expression in them.


RESULTS
Dex, a GR agonist, decreased ABCA1 mRNA levels in a dose- and time-dependent fashion, and RU486, a GR antagonist, reversed the inhibitory effect of Dex. The effects of Dex and RU486 on ABCA1 protein levels and apolipoprotein AI-mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels. Transfected RAW264.7, together with a human ABCA1 promoter-luciferase construct, inhibited transcriptional activity by Dex and overexpression of human GR. Transrepression by GR was not mediated by liver X receptor (LXR), because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations, and no changes were brought about in ABCG1 and ABCG4 expression by GR ligands.


CONCLUSIONS
Our results showed that GR ligands affected ABCA1 expression and cholesterol efflux from macrophages, which are regulated by GR through a LXR-independent mechanism.
Ayaori
Makoto
M
First Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan. ayaori@ba2.so-net.ne.jp
Sawada
Shojiro
S
Yonemura
Atsushi
A
Iwamoto
Noriyuki
N
Ogura
Masatsune
M
Tanaka
Nobukiyo
N
Nakaya
Kazuhiro
K
Kusuhara
Masatoshi
M
Nakamura
Haruo
H
Ohsuzu
Fumitaka
F
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D006727:Hormone Antagonists; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D002784:Cholesterol