Atorvastatin decreases lipoprotein lipase and endothelial lipase expression in human THP-1 macrophages.
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.
Qiu
Guosong
G
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, BC, Canada.
Hill
John S
JS
D000818:Animals; D000069059:Atorvastatin; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008049:Lipase / Q000096:biosynthesis*; D008071:Lipoprotein Lipase / Q000096:biosynthesis*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis*; D057093:Orphan Nuclear Receptors; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology
D004268:DNA-Binding Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C410382:LIPG protein, human; D008049:Lipase; D008071:Lipoprotein Lipase