REGULAR ARTICLES

Cell Research (2004); 14(4): 315-323

Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone

Li YANG¹, Jin Bo YANG¹, Jia CHEN¹, Guang Yao YU¹, Pei ZHOU¹, Lei LEI¹, Zhen Zhen WANG¹, Catherine CY CHANG, XinYing YANG¹, Ta Yuan CHANG^2,*, Bo Liang LI^1,*

¹State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China.
²Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03756; USA.

Received, Jan 19, 2004    Revised, June 31, 2004    Accepted, July 5, 2004

Correspondence: Ta Yuan CHANG (603)-650-1622 (phone) (603)-650-1483 (fax) Ta.Yuan.Chang@dartmouth.edu and Bo Liang LI (86)-21-5492-1278 (phone) (86)-21-5492-1279 (fax) blli@sibs.ac.cn

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Abstract

In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.

Keywords: ACAT, dexamethasone, macrophage, cholesteryl ester, gene promoter.