Novel Keto-phospholipids Are Generated by Monocytes and Macrophages, Detected in Cystic Fibrosis, and Activate Peroxisome Proliferator-activated Receptor-γ

Abstract

Background: Lipoxygenases (LOXs) generate eicosanoids in inflammation.Results: Monocyte/macrophage LOXs generate novel phospholipid-esterified eicosanoids containing ketoeicosatetraenoic acid or hydroperoxyeicosatetraenoic acid. They activate peroxisome proliferator-activated receptor-γ transcriptional activity and are found in cystic fibrosis bronchoalveolar fluid.Significance: LOXs generate esterified eicosanoids in vitro and in vivo.Conclusion: These new lipids represent new families of bioactive mediators.

Oxidative Lipidomics Coming of Age: Advances in Analysis of Oxidized Phospholipids in Physiology and Pathology

“…Oxidized PEs were found to occur in bronchoaveolar lavage fluid from patients with lung diseases, using negative ion MS analysis (42). Precursor ion scanning was used as a discovery tool to find precursors of m/z 317.2 (KETEcontaining lipids).…”

“…Patients with cystic fibrosis had significantly higher levels of three oxidized plasmenyl phosphoethanolamines: 18:0p/15-KETE-PE, 18:1p/15-KETE-PE, and 16:0p/15-KETE-PE, at levels from approximately 0.05 to 3.5 ng/ml; although similar levels of the ester-linked compound 18:0a/15-KETE-PE were observed, the difference was not significant. The HETEand KETE-containing PEs are mainly generated by the action of 15-lipoxygenase in macrophages, and they were shown to cause stimulation of PPARc and upregulate CD36 expression in peritoneal macrophages (42). The increased levels of these oxidized lipids are thought to have a role in damping down the acute pulmonary inflammation characteristic of cystic fibrosis and may offer therapeutic potential for treating the disease.…”

Toll-like receptor 4 senses oxidative stress mediated by the oxidation of phospholipids in extracellular vesicles

“…Although most of the 15-H(p)ETE from activated monocytes belong to the PE phospholipid class (53), it is likely that 15-(p)ETE compounds with other phospholipid head groups can act as TLR4 agonists, because we detected the binding of several anionic phospholipids to MD-2. Also, we speculate that structurally similar 15-ketoeicosatetraenoic acid-phosphatidyethanolamines (15-KETE-PEs), which activate peroxisome proliferator-activated receptor-g (56), might act as TLR4 agonists. Our results suggest that lipoxygenases may act as a link between oxidative stress and the (patho)physiological role of TLR4.…”

Directing eicosanoid esterification into phospholipids

“…To characterize the molecular species of complex lipids, precursor scanning LC-MS/MS was used, thus "fishing" for molecular ions that incorporated a HETE functional group. Between 2007 and 2012, several families of eoxPLs generated by LOXs were uncovered using this approach, not only in monocytes but also in human platelets, neutrophils, and airway epithelial cells (9)(10)(11)(12)(13)(14). The most abundant were phosphatidylethanolamines (PEs) but PC-derived forms were detected with many being plasmalogens.…”

“…In tissues, the eoxPL profile reflects the oxidative enzymes expressed; for example, cells expressing 15-LOX generate PL that incorporate 15-HETE or 15-ketoeicosatetraenoic acid (KETE), the latter via prostaglandin dehydrogenase activity downstream of 15-LOX (8,10). In platelets, 12-HETE or 14-HDOHE attached to PE or PC are found, whereas EET-PLs in liver predominate as positional isomers reflecting cytochrome P-450 activities (5,12,13).…”