Submitted on December 1, 2006
Revised on July 6, 2007
Accepted on July 19, 2007
Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages
Guosong Qiu and John S. Hill
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6
Corresponding Author: 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 lipoprotein lipase (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, LXR and nuclear factor kappa B (NF-B) activation in THP-1 macrophages. Atorvastatin-reduced LPL and EL expression was only partially recovered by mevalonate co-treatment 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 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 inhibition by 22(S)-hydroxycholesterol decreased LPL expression. By contrast, EL expression was suppressed by LXR activation in the presence or absence of atorvastatin. NF-B inhibition by SN50 was associated with a ~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 and NF-kB, respectively.
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