Synergism Between Platelet-Activating Factor-Like Phospholipids and Peroxisome Proliferator-Activated Receptor γ Agonists Generated During Low Density Lipoprotein Oxidation That Induces Lipid Body Formation in Leukocytes

Abstract

Oxidized low density lipoprotein (LDL) has an important proinflammatory role in atherogenesis. In this study, we investigated the ability of oxidized LDL (oxLDL) and its phospholipid components to induce lipid body formation in leukocytes. Incubation of mouse peritoneal macrophages with oxidized, but not with native LDL led to lipid body formation within 1 h. This was blocked by platelet-activating factor (PAF) receptor antagonists or by preincubation of oxLDL with rPAF acetylhydrolase. HPLC fractions of phospholipids purified from oxLDL induced calcium flux in neutrophils as well as lipid body formation in macrophages. Injection of the bioactive phospholipid fractions or butanoyl and butenoyl PAF, a phospholipid previously shown to be present in oxLDL, into the pleural cavity of mice induced lipid body formation in leukocytes recovered after 3 h. The 5-lipoxygenase and cyclooxygenase-2 colocalized within lipid bodies formed after stimulation with oxLDL, bioactive phospholipid fractions, or butanoyl and butenoyl PAF. Lipid body formation was inhibited by 5-lipoxygenase antagonists, but not by cyclooxygenase-2 inhibitors. Azelaoyl-phosphatidylcholine, a peroxisome proliferator-activated receptor-γ agonist in oxLDL phospholipid fractions, induced formation of lipid bodies at late time points (6 h) and synergized with suboptimal concentrations of oxLDL. We conclude that lipid body formation is an important proinflammatory effect of oxLDL and that PAF-like phospholipids and peroxisome proliferator-activated receptor-γ agonists generated during LDL oxidation are important mediators in this phenomenon.

Leptin and mTOR: Partners in metabolism and inflammation

“…40,82 Macrophage lipid bodies, which are formed by different stimuli and pathological conditions including obesity-induced inflammation, ox-LDL-and LPS-induced inflammation or bacterial infection, are increasingly recognized as organelles with key roles in inflammation. [83][84][85][86][87][88] Under inflammatory conditions, they compartmentalize MAP kinases, cPLA 2 , eicosanoid-forming enzymes and are involved in the enhanced eicosanoid synthesis. [84][85][86][87][88][89] In addition, human colon adenocarcinoma cell lines and colon cancer biopsies from patients have recently been shown to exhibit a drastic increase in ADRP and COX-2-enriched lipid bodies.…”

Mechanisms of leukocyte lipid body formation and function in inflammation

“…Indeed, stimuli known to prime leukocytes to induce eicosanoid generation, including PKC activators, arachidonate and PAF, are also active in stimulating lipid body formation. Accordingly, others and we observed a significant correlation between lipid body formation and enhanced generation of both LO-and COX- derived eicosanoids in vitro (Bozza et al 1996a, b, 1997, Bartmenes et al 1999 as well as in vivo , Silva et al 2002, de Assis et al 2003. Analogously, agents that inhibited lipid body formation also resulted in inhibited priming for eicosanoid production.…”

“…Indeed, we observed that treatment of mouse macrophages with BRL 49653, a preferential PPARγ ligand, failed to induce lipid body formation. However, BRL 49653 treatment significantly potentiated lipid body formation induced by ox-LDL or PAF-like agonists, suggesting that PPAR have a role in regulating leukocyte lipid body formation (de Assis et al 2003). However, we anticipate that differences in PPAR expression and role in lipid body formation may vary according to the cell type and stimuli studied and further studies are needed to characterize the roles of PPAR in lipid body formation and the involvement of PPAR targeted genes in this phenomenon.…”

“…Lipid bodies, in both ox-LDL-and LPS-induced models of inflammation, compartmentalize 5-LO and COX-2 enzymes within recruited leukocytes , de Assis et al 2003. Similarly, eosinophils attracted to the site of allergic reaction showed 5-LO and COX-2 immuno-reactivity within newly formed lipid bodies.…”

“…Moreover, PAF but not its precursor and metabolite, lyso-PAF, that shares the lipid structure of PAF but has no receptor agonistic activity (Prescott et al 2000), have the capacity to induce lipid body formation (Bozza et al 1996a, 1997, de Assis et al 2003. In addition, it has been demonstrated that PAF-induced lipid body formation in leukocytes involves the regulated activation of different signaling pathways (Fig.…”