J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M600510-JLR200 on July 20, 2007

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Journal of Lipid Research, Vol. 48, 2112-2122, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages

Guosong Qiu and John S. Hill1

Atherosclerosis Specialty Laboratory, Healthy Heart Program, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6Z 1Y6, Canada

Published, JLR Papers in Press, July 20, 2007.

1 To whom correspondence should be addressed. e-mail: jshill{at}interchange.ubc.ca

Macrophage-derived lipases are associated with atherosclerosis in human and animal studies. Despite numerous non-lipid-lowering effects of statins, their effect on macrophage LPL and endothelial lipase (EL) expression has not been investigated. In the present study, atorvastatin and simvastatin dose-dependently decreased LPL and EL expression as well as Rho, liver X receptor {alpha} (LXR{alpha}), and nuclear factor {kappa}B (NF-{kappa}B) activation in THP-1 macrophages. Atorvastatin-reduced LPL and EL expression was only partially recovered by mevalonate cotreatment, indicating that mechanisms independent of reductase inhibition may be present. By contrast, Rho activation by lysophosphatidyl acid further decreased LPL and EL expression in the presence or absence of atorvastatin. Another Rho activator, farnysyl pyrophosphate, decreased EL expression only in the absence of atorvastatin. LXR{alpha} activation by T0901317 and 22(R)-hydroxycholesterol not only rescued but also significantly increased LPL expression in the presence and absence of atorvastatin, respectively, whereas LXR{alpha} inhibition by 22(S)-hydroxycholesterol decreased LPL expression. By contrast, EL expression was suppressed by LXR{alpha} activation in the presence or absence of atorvastatin. NF-{kappa}B inhibition by SN50 was associated with an ~30% reduction of EL expression. Furthermore, atorvastatin treatment significantly attenuated the lipid accumulation in macrophages treated with oxidized LDL. We conclude that atorvastatin reduces LPL and EL expression by reducing the activation of LXR{alpha} and NF-{kappa}B, respectively.

Supplementary key words 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor • simvastatin • Rho protein • liver X receptor • nuclear factor {kappa}B


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