Group X secretory phospholipase a2 regulates insulin secretion through a cyclooxygenase-2-dependent mechanism

Preetha Shridas, Lubna Zahoor, Kathy J. Forrest, Joseph D. Layne, Nancy R. Webb

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Group X secretory phospholipase A2 (GX sPLA2) potently hydrolyzes membrane phospholipids to release arachidonic acid (AA). While AA is an activator of glucose-stimulated insulin secretion (GSIS), its metabolite prostaglandin E2 (PGE2) is a known inhibitor. In this study, we determined that GX sPLA2 is expressed in insulin-producing cells of mouse pancreatic islets and investigated its role in beta cell function. GSIS was measured in vivo in wild-type (WT) and GX sPLA2-deficient (GX KO) mice and ex vivo using pancreatic islets isolated from WT and GX KO mice. GSIS was also assessed in vitro using mouse MIN6 pancreatic beta cells with or without GX sPLA2 overexpression or exogenous addition. GSIS was significantly higher in islets isolated from GX KO mice compared with islets from WT mice. Conversely, GSIS was lower in MIN6 cells overexpressing GX sPLA2 (MIN6-GX) compared with control (MIN6-C) cells. PGE2 production was significantly higher in MIN6-GX cells compared with MIN6-C cells and this was associated with significantly reduced cellular cAMP. The effect of GX sPLA2 on GSIS was abolished when cells were treated with NS398 (a COX-2 inhibitor) or L-798,106 (a PGE2-EP3 receptor antagonist). Consistent with enhanced beta cell function, GX KO mice showed significantly increased plasma insulin levels following glucose challenge and were protected from age-related reductions in GSIS and glucose tolerance compared with WT mice. We conclude that GX sPLA2 plays a previously unrecognized role in negatively regulating pancreatic insulin secretion by augmenting COX-2-dependent PGE2 production.

Original languageEnglish
Pages (from-to)27410-27417
Number of pages8
JournalJournal of Biological Chemistry
Volume289
Issue number40
DOIs
StatePublished - Oct 3 2014

Bibliographical note

Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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