title: Glucocorticoid receptor regulates ATP-binding cassette transporter-A1 expression and apolipoprotein-mediated cholesterol efflux from macrophages.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan. ayaori@ba2.so-net.ne.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonemura
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Nobukiyo
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kusuhara
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
mesh_terms: 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
chemical_list: 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