Phospholipase A ₂ –Modified Low-Density Lipoprotein Activates Macrophage Peroxisome Proliferator–Activated Receptors

Abstract

Background and Purpose-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). Methods and Results-By analyzing PPAR ligand-binding domain luciferase reporter activation, we observed that PLA-LDL transactivates PPAR␣ and PPAR␦, but not PPAR␥. We confirmed that PLA-LDL induced PPAR response element reporter activation by endogenous PPAR␣ and PPAR␦ in human THP-1 macrophages. 1 Foam cell formation is usually associated with signs of inflammation, and inflammation accompanies atherosclerosis through all stages of lesion progression. 2 However, on uptake of lipoproteins, macrophages also exhibit homeostatic responses to lower lipid accumulation and to attenuate inflammation. The nuclear receptor family of peroxisome proliferator-activated receptors (PPARs), consisting of PPAR␣, PPAR␥, and PPAR␦, plays an important role in regulating lipid metabolism and inflammation in macrophages and other vascular cells. 3 The activation of PPARs was described for oxidized low-density lipoprotein (oxLDL), 4,5 oxidized phospholipids, 6 or very LDL (VLDL). 7 The lipolysis of lipoproteins (eg, by lipoprotein lipase [LPL] or endothelial lipase) may also generate potent PPAR ligands. 7-10 A consequence of PPAR activation is enhanced cholesterol efflux from macrophages 5,11 and reduced inflammation. 12 Initially, only PPAR␣ and PPAR␥ were ascribed a clear antiatherosclerotic effect, 13 whereas some ambiguity existed about the contribution of PPAR␦ to atherosclerosis development, given its positive involvement in macrophage lipid accumulation 14 and the antiatherosclerotic effects of PPAR␦ gene deletion. 15 However, recent studies 16,17 clearly showed antiatherogenic effects of PPAR␦, especially under proinflammatory conditions. In addition, PPAR␥ and PPAR␦ activation favors a macrophage phenotype switch towards an alternatively activated M2 phenotype. 18 This macrophage phenotype switch is supposed to reduce inflammation and contribute to the beneficial effects of PPAR agonists to ameliorate insulin resistance and possibly atherosclerosis. 19 -22 LDL modified by secretory phospholipase A 2 (PLA-LDL) is readily taken up by macrophages, resulting in foam cell formation. 23,24 These events underlie a well-described proatherogenic action of secretory phospholipases A 2 . 25,26 The intracellular mechanisms accompanying PLA-LDL-induced foam cell formation are less understood. In monocytic cells, we noticed that PLA-LDL activated the cytoprotective phosphatidylinositol 3-kinase-Akt pathway, which was attributed to PLA-LDLassociated nonesterified fatty acids (NEFAs). 27 Here we report that PLA-LDL, via its associated NEFA, activates PPAR␣ and PPAR␦ in human macrophages. MethodsFor a description of oil red staining, intracellular cholesterol and triglyceride a...

Group X Secretory Phospholipase A 2 Negatively Regulates ABCA1 and ABCG1 Expression and Cholesterol Efflux in Macrophages

“…The possibility that sPLA 2 can also provide lipid mediators (FFAs, prostaglandins) that serve as ligands for PPARs cannot be ruled out; however, evidence that this occurs is currently controversial 32-34. We found no evidence that CD36 or aP2, known PPAR-γ targets, was regulated by GX sPLA 2 .…”

The Adipocyte-Inducible Secreted Phospholipases PLA2G5 and PLA2G2E Play Distinct Roles in Obesity

“…This action of PLA2G5 depends on its capacity to hydrolyze phospholipids in LDL to release unsaturated fatty acids, which can allow the polarization shift of macrophages from the M1 to M2 state. Reportedly, fatty acids released from lipoproteins by venom sPLA 2 or lipoprotein lipase can facilitate anti-inflammatory responses in vitro (Ahmed et al, 2006; Duncan et al, 2010; Namgaladze et al, 2010). Herein, we demonstrate that unsaturated fatty acids including OA > LA, which are supplied by PLA2G5-driven hydrolysis of PC in hyperlipidemic LDL, prevent PA-induced M1 macrophage polarization likely through attenuating the ER stress, revealing a functional link between lipoprotein metabolism and anti-inflammation by this sPLA 2 .…”

Bioactive products generated by Group V sPLA2 hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines

“…Although sPLA 2 's can generate lipid mediators (FFAs, prostaglandins) that are potential PPAR ligands, evidence that this occurs is controversial [40, 42-43]. In the case of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) the enzyme effectively hydrolyzes truncated acyl chains present on oxidatively modified LDL to release lyso-phosphatidylcholine and oxidized FFAs [44].…”