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

摘要

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 similar to 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.