The dual role of group V secretory phospholipase A2 in pancreatic β-cells
- First Online:
Group X (GX) and group V (GV) secretory phospholipase A2 (sPLA2) potently release arachidonic acid (AA) from the plasma membrane of intact cells. We previously demonstrated that GX sPLA2 negatively regulates glucose-stimulated insulin secretion (GSIS) by a prostaglandin E2 (PGE2)-dependent mechanism. In this study we investigated whether GV sPLA2 similarly regulates GSIS.
GSIS and pancreatic islet-size were assessed in wild-type (WT) and GV sPLA2-knock out (GV KO) mice. GSIS was also assessed ex vivo in isolated islets and in vitro using MIN6 pancreatic beta cell lines with or without GV sPLA2 overexpression or silencing.
GSIS was significantly decreased in islets isolated from GV KO mice compared to WT mice and in MIN6 cells with siRNA-mediated GV sPLA2 suppression. MIN6 cells overexpressing GV sPLA2 (MIN6-GV) showed a significant increase in GSIS compared to control cells. Though the amount of AA released into the media by MIN6-GV cells was significantly higher, PGE2 production was not enhanced or cAMP content decreased compared to control MIN6 cells. Surprisingly, GV KO mice exhibited a significant increase in plasma insulin levels following i.p. injection of glucose compared to WT mice. This increase in GSIS in GV KO mice was associated with a significant increase in pancreatic islet size and number of proliferating cells in β-islets compared to WT mice.
Deficiency of GV sPLA2 results in diminished GSIS in isolated pancreatic beta-cells. However, the reduced GSIS in islets lacking GV sPLA2 appears to be compensated by increased islet mass in GV KO mice.
KeywordsGV sPLA2 Type 2 diabetes Insulin secretion Arachidonic acid β-islet mass
- 6.M.E. Kimple, M.P. Keller, M.R. Rabaglia, R.L. Pasker, J.C. Neuman, N.A. Truchan, H.K. Brar, A.D. Attie, Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes 62, 1904–1912 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
- 20.C.M. Mounier, F. Ghomashchi, M.R. Lindsay, Arachidonic acid release from mammalian cells transfected with human groups IIA and X secreted phospholipase A(2) occurs predominantly during the secretory process and with the involvement of cytosolic phospholipase A(2)-alpha. J. Biol. Chem. 279, 25024–25038 (2004)CrossRefPubMedGoogle Scholar
- 22.Y. Satake, B.L. Diaz, B. Balestrieri, B.K. Lam, Y. Kanaoka, M.J. Grusby, J.P. Arm, Role of group V phospholipase A2 in zymosan-induced eicosanoid generation and vascular permeability revealed by targeted gene disruption. J. Biol. Chem. 279, 16488–16494 (2004)CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Z. Meng, J. Lv, Y. Luo, Y. Lin, Y. Zhu, J. Nie, T. Yang, Y. Sun, X. Han, Forkhead box O1/pancreatic and duodenal homeobox 1 intracellular translocation is regulated by c-Jun N-terminal kinase and involved in prostaglandin E2-induced pancreatic β-cell dysfunction. Endocrinology 150, 5284–5293 (2009)CrossRefPubMedGoogle Scholar
- 34.A.G. Singer, F. Ghomashchi, C. Le Calvez, J. Bollinger, S. Bezzine, M. Rouault, M. Sadilek, E. Nguyen, M. Lazdunski, G. Lambeau, M.H. Gelb, Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X, and XII secreted phospholipases A2. J. Biol. Chem. 277, 48535–48549 (2002)CrossRefPubMedGoogle Scholar
- 39.M. Rouault, C. Le Calvez, E. Boilard, F. Surreal, A. Singer, F. Ghomashchi, S. Bezzine, S. Scarzello, M.H. Gelb, G. Lambeau, Recombinant production and properties of binding of the full set of mouse secreted phospholipases A2 to the mouse M-type receptor. Biochemistry 46, 1647–1662 (2007)CrossRefPubMedGoogle Scholar
- 40.Y. Morioka, A. Saiga, Y. Yokota, N. Suzuki, M. Ikeda, T. Ono, K. Nakano, N. Fujiii, J. Ischizaki, H. Arita, K. Hanasaki, Mouse group x secretory phospholipase A2 induces a potent release of arachidonic acid from spleen cells and acts as a ligand for the phospholipase A2 Receptor. Arch. Biochem. Biophys. 381, 31–42 (2000)CrossRefPubMedGoogle Scholar
- 42.B. Rosengren, H. Peilot, M. Umaerus, A.C. Jonsson-Rylander, L. Mattsson-Halten, C. Hallberg, P. Cronet, M. Rodriquez-Lee, E. Hurt-Camejo, Secretory phospholipase A2 group V: lesion distribution, activation by arterial proteoglycans, and induction in aorta by a western diet. Arterioscler. Thromb. Vasc. Biol. 26, 1579–1585 (2006)CrossRefPubMedGoogle Scholar
- 43.M. Murakami, R.S. Koduri, A. Enomoto, S. Shimbara, M. Seki, K. Yoshihara, A. Singer, E. Valentin, F. Ghomashchi, G. Lambeau, M.H. Gelb, I. Kudo, Distinct arachidonate-releasing functions of mammalian secreted phospholipase A2s in human embryonic kidney 293 and rat mastocytoma RBL-2H3 cells through heparan sulfate shuttling and external plasma membrane mechanisms. J. Biol. Chem. 276, 10083–10096 (2001)CrossRefPubMedGoogle Scholar
- 44.J.D. Layne, P. Shridas, N.R. Webb, Ectopically expressed pro-group X secretory phospholipase A2 is proteolytically activated in mouse adrenal cells by furin-like proprotein convertases: implications for the regulation of adrenal steroidogenesis. J. Biol. Chem. 290, 7851–7860 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
- 45.I. Jemel, H. Ii, R.C. Oslund, C. Payre, A.S. Dabert-Gay, D. Douquet, K. Charqui, S. Scarzello, M.H. Gelb, G. Lambeau, Group x secreted phospholipase A2 proenzyme is matured by a furin-like proprotein convertase and releases arachidonic acid inside of human HEK293 cells. J. Biol. Chem. 286, 36509–36521 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
- 47.H. Sato, Y. Taketomi, A. Ushida, Y. Isogai, T. Kojima, T. Hirabayashi, Y. Miki, K. Yamamoto, Y. Nishito, T. Kobayashi, K. Ikeda, R. Taguchi, S. Hara, S. Ida, Y. Miyamoto, M. Watanabe, H. Baba, K. Miyata, Y. Oike, M.H. Gelb, M. Murakami, The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. Cell Metab. 20, 119–132 (2014)CrossRefPubMedPubMedCentralGoogle Scholar