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 atherosclerosisin human and animal studies. Despite numerous non-lipid-loweringeffects of statins, their effect on macrophage LPL and endotheliallipase (EL) expression has not been investigated. In the presentstudy, atorvastatin and simvastatin dose-dependently decreasedLPL 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 partiallyrecovered by mevalonate cotreatment, indicating that mechanismsindependent of reductase inhibition may be present. By contrast,Rho activation by lysophosphatidyl acid further decreased LPLand EL expression in the presence or absence of atorvastatin.Another Rho activator, farnysyl pyrophosphate, decreased ELexpression only in the absence of atorvastatin. LXR ${alpha}$ activationby T0901317 and 22(R)-hydroxycholesterol not only rescued butalso significantly increased LPL expression in the presenceand absence of atorvastatin, respectively, whereas LXR ${alpha}$ inhibitionby 22(S)-hydroxycholesterol decreased LPL expression. By contrast,EL expression was suppressed by LXR ${alpha}$ activation in the presenceor absence of atorvastatin. NF- ${kappa}$ B inhibition by SN50 was associatedwith an $~$ 30% reduction of EL expression. Furthermore, atorvastatintreatment significantly attenuated the lipid accumulation inmacrophages treated with oxidized LDL. We conclude that atorvastatinreduces LPL and EL expression by reducing the activation ofLXR ${alpha}$ 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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