TY - JOUR
T1 - Cyclooxygenase-2 Mediated Oxidation of 2-Arachidonoyl-Lysophospholipids Identifies Unknown Lipid Signaling Pathways
AU - Liu, Xinping
AU - Moon, Sung Ho
AU - Jenkins, Christopher M.
AU - Sims, Harold F.
AU - Gross, Richard W.
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/10/20
Y1 - 2016/10/20
N2 - 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, iPLA2γ, 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 iPLA2γ−/− fibroblasts. Collectively, these results identify an iPLA2γ-initiated pathway generating new classes of lipid metabolites with potential signaling functions resulting from the direct COX-2 catalyzed oxidation of 2-arachidonoyl-lysolipids.
AB - 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, iPLA2γ, 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 iPLA2γ−/− fibroblasts. Collectively, these results identify an iPLA2γ-initiated pathway generating new classes of lipid metabolites with potential signaling functions resulting from the direct COX-2 catalyzed oxidation of 2-arachidonoyl-lysolipids.
UR - http://www.scopus.com/inward/record.url?scp=84992350006&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2016.08.009
DO - 10.1016/j.chembiol.2016.08.009
M3 - Article
C2 - 27642067
AN - SCOPUS:84992350006
SN - 2451-9456
VL - 23
SP - 1217
EP - 1227
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 10
ER -