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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:163.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Glucocorticoid Receptor Regulates ATP-Binding Cassette Transporter-A1 Expression and Apolipoprotein-Mediated Cholesterol Efflux From Macrophages

Makoto Ayaori; Shojiro Sawada; Atsushi Yonemura; Noriyuki Iwamoto; Masatsune Ogura; Nobukiyo Tanaka; Kazuhiro Nakaya; Masatoshi Kusuhara; Haruo Nakamura; Fumitaka Ohsuzu

From the First Department of Internal Medicine (M.A., S.S., A.Y., N.I., M.O., N.T., K.N., M.K., F.O.), National Defense Medical College, Tokorozawa, and the Mitsukoshi Health and Welfare Foundation (H.N.), Tokyo, Japan.

Correspondence to Makoto Ayaori, First Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan 359-8513. E-mail ayaori{at}ba2.so-net.ne.jp

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.

Methods and 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.

Several nuclear receptors regulate ABCA1 expression to maintain intracellular cholesterol. The present study showed that glucocorticoid receptor (GR) agonist and antagonist, respectively, attenuated and stimulated cholesterol efflux from macrophages by apolipoprotein and ABCA1 expression, which are regulated by GR at a transcriptional level through an LXR-independent mechanism.

Key Words: ABCA1 • dexamethasone • GR • cholesterol • macrophage

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