Cyclooxygenase-2 Mediated Oxidation of 2-Arachidonoyl-Lysophospholipids Identifies Unknown Lipid Signaling Pathways. Issue 10 (20th October 2016)

• Record Type: Journal Article
• Authors: Liu, Xinping; Moon, Sung Ho; Jenkins, Christopher M.; Sims, Harold F.; Gross, Richard W.
• Is Part Of: Cell chemical biology. Volume 23:Issue 10(2016)
• Page Start: 1217
• Page End: 1227
• Publication Date: 2016-10-20
• Subjects: Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.08.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Eicosanoid lipids play important roles in cellular signaling as second messengers in inflammation, immune response, vascular tone, and the CNS. Biosynthesis of eicosanoid lipids proceeds via hydrolysis of esterified arachidonic acid from phospholipids followed by oxidation of the released arachidonic acid by a variety of enzymes including cyclooxygenases (COX). Herein, we demonstrate the remarkable ability of COX-2, but not COX-1, to directly oxidize 2-arachidonoyl-lysolipids, resulting in the generation of previously unknown classes of eicosanoid-lysolipids, and provide evidence that intracellular lipases can release eicosanoids from their eicosanoid-lysolipid precursors. Importantly, genetic ablation of a phospholipase, iPLA2 γ, significantly reduced the amounts of these eicosanoid-lysolipids in murine hepatic tissue and fibroblasts. Furthermore, calcium stimulation of wild-type murine lung fibroblasts produced robust increases in these eicosanoid-lysolipids, which were markedly attenuated in iPLA2 γ −/− fibroblasts. Collectively, these results identify an iPLA2 γ-initiated pathway generating new classes of lipid metabolites with potential signaling functions resulting from the direct COX-2 catalyzed oxidation of 2-arachidonoyl-lysolipids. Graphical Abstract: Highlights: COX-2 directly oxidizes 2-arachidonoyl-lysophospholipids to eicosanoid-lysolipids Lipases (e.g., cPLA2 α) release eicosanoids from eicosanoid-lysolipid precursors Genetic ablation of iPLA2 γ reduces the amounts of eicosanoid-lysolipids Calcium stimulation robustly increases the production of eicosanoid-lysolipids Abstract : Liu et al. demonstrate the previously unrecognized ability of COX-2, but not COX-1, to directly oxidize 2-arachidonoyl-lysolipids produced by iPLA2 γ to generate multiple novel eicosanoid-lysolipids that can be hydrolyzed by known intracellular lipases (e.g., cPLA2 α) to generate non-esterified eicosanoids.