Abstract
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 (LXRalpha), and nuclear factor kappaB (NF-kappaB) 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. LXRalpha 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 LXRalpha inhibition by 22(S)-hydroxycholesterol decreased LPL expression. By contrast, EL expression was suppressed by LXRalpha activation in the presence or absence of atorvastatin. NF-kappaB inhibition by SN50 was associated with an approximately 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 LXRalpha and NF-kappaB, respectively.
Highlights
Macrophage-derived lipases are associated with atherosclerosis in human and animal studies
THP-1-derived macrophages were treated under variable concentrations of atorvastatin in a range from 2 to 40 mM, which reduced HMG-CoA reductase activity by 38% at 2 mM, 47% at 10 mM, and 66% at 20 mM
LPL mRNA was decreased by 56% and endothelial lipase (EL) mRNA was decreased by 63% at 20 mM atorvastatin (Fig. 1B)
Summary
Macrophage-derived lipases are associated with atherosclerosis in human and animal studies. Atorvastatin and simvastatin dose-dependently decreased LPL and EL expression as well as Rho, liver X receptor a (LXRa), and nuclear factor kB (NF-kB) activation in THP-1 macrophages. Rho activation by lysophosphatidyl acid further decreased LPL and EL expression in the presence or absence of atorvastatin. LXRa activation by T0901317 and 22(R)-hydroxycholesterol rescued and significantly increased LPL expression in the presence and absence of atorvastatin, respectively, whereas LXRa inhibition by 22(S)-hydroxycholesterol decreased LPL expression. Conflicting results were reported with regard to the influence of EL in mouse models of atherosclerosis [13, 14], an increase of EL protein was found in human subjects with the metabolic syndrome, and in a separate cohort, plasma EL levels were associated with the concentration of inflammatory markers [15, 16]. HMG-CoA reductase inhibitors (satins) effectively reduce cholesterol and apoB-containing lipoprotein levels by blocking the endogenous cholesterol synthesis through the competitive inhibition of HMG-CoA reductase, and they are used extensively in the treatment of hypercholes-
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