Journal of Biological Chemistry
Volume 285, Issue 43, 22 October 2010, Pages 33499-33509
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Lipids
Adenosine Monophosphate-activated Protein Kinase Induces Cholesterol Efflux from Macrophage-derived Foam Cells and Alleviates Atherosclerosis in Apolipoprotein E-deficient Mice*,

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Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis-related genes. The up-regulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3′-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE−/− mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE−/− mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK.

ABC Transporter
AMP-activated kinase (AMPK)
Atherosclerosis
Cholesterol Metabolism
Macrophage

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*

This work was supported by National Natural Science Foundation Grants 30730079 and 30700665, Guangdong Natural Science Foundation Grant 9151012003000002, Foundation for the Author of National Excellent Doctoral Dissertation of China Grant 200978, Research Fund for the Doctoral Program of Higher Education of China Grant 20070558276, and the Fundamental Research Funds for the Central Universities of Sun Yat-Sen University 10ykzd04.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

1

These authors contributed equally to this work.