Phospholipase A2-modified low-density lipoprotein activates macrophage peroxisome proliferator-activated receptors.
OBJECTIVE
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors modulating metabolic and inflammatory responses of phagocytes to stimuli such as fatty acids and their metabolites. We studied the role of PPARs in macrophages exposed to low-density lipoprotein (LDL) modified by secretory phospholipase A(2) (PLA).


RESULTS
By analyzing PPAR ligand-binding domain luciferase reporter activation, we observed that PLA-LDL transactivates PPARalpha and PPARdelta, but not PPARgamma. We confirmed that PLA-LDL induced PPAR response element reporter activation by endogenous PPARalpha and PPARdelta in human THP-1 macrophages. By using THP-1 cells with a stable knockdown of PPARalpha and PPARdelta, we showed that PLA-LDL-activated PPARdelta altered macrophage gene expression related to lipid metabolism and lipid droplet formation. Although PPARalpha/delta silencing did not affect cholesterol and triglyceride accumulation in PLA-LDL-treated macrophages, PPARdelta activation by PLA-LDL attenuated macrophage inflammatory gene expression induced by interferon gamma and lipopolysaccharide.


CONCLUSIONS
PPARdelta activation by PLA-LDL does not influence lipid accumulation in PLA-LDL-treated macrophages. However, it attenuates macrophage inflammatory responses, thus contributing to an anti-inflammatory cell phenotype.
Namgaladze
Dmitry
D
Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I/ZAFES, Frankfurt, Germany. bruene@pathobiochemie1.de
Morbitzer
Daniel
D
von Knethen
Andreas
A
Brüne
Bernhard
B
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma; D002784:Cholesterol; D054497:Phospholipases A2, Secretory