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The dual role of group V secretory phospholipase A2 in pancreatic β-cells

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  1. M. Prentki, C.J. Nolan, Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. S. Ramanadham, R.W. Gross, X. Han, J. Turk, Inhibition of arachidonate release by secretagogue-stimulated pancreatic islets suppresses both insulin secretion and the rise in beta-cell cytosolic calcium ion concentration. Biochemistry 32, 337–346 (1993)

    Article  CAS  PubMed  Google Scholar 

  3. S. Ramanadham, H. Song, S. Bao, F.F. Hsu, S. Zhang, Z. Ma, C. Jin, J. Turk,Islet complex lipids: involvement in the actions of group VIA calcium-independent phospholipase A(2) in beta-cells.Diabetes 53(Suppl 1),S179–S185 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. R. Robertson, R.P. Tsai, P. Little, S.A. Zhang, H.J. Walseth, T.F. Receptor-mediated, Adenylate cyclase-coupled mechanism for PGE2 inhibition of insulin secretion in HIT cells. Diabetes 36, 1047–1053 (1987)

    Article  CAS  PubMed  Google Scholar 

  5. A. Sjoholm, Prostaglandins inhibit pancreatic beta-cell replication and long-term insulin secretion by pertussis toxin-insensitive mechanisms but do not mediate the actions of interleukin-1 beta. Biochim. Biophys. Acta 1313, 106–110 (1996)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. E.R. Seaquist, T.F. Walseth, D.M. Nelson, R.P. Robertson, Pertussis toxin-sensitive G protein mediation of PGE2 inhibition of cAMP metabolism and phasic glucose-induced insulin secretion in HIT cells. Diabetes 38, 1439–1445 (1989)

    Article  CAS  PubMed  Google Scholar 

  8. P.O. Tran, C.E. Gleason, V. Poitout, R.P. Robertson, Prostaglandin E2 mediates inhibition of insulin secretion by interleukin-1β. J. Biol. Chem. 274, 31245–31248 (1999)

    Article  CAS  PubMed  Google Scholar 

  9. H. Fujita, M. Kakei, H. Fujishima, T. Morii, Y. Yamada, Z. Qi, M.D. Breyer, Effect of selective cyclooxygenase-2 (COX-2) inhibitor treatment on glucose-stimulated insulin secretion in C57BL/6 mice. Biochem. Biophys. Res. Commun. 363, 37–43 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. E.M. Smyth, T. Grosser, M. Wang, Y. Yu, G.A. FitzGerald, Prostanoids in health and disease. J. Lipid Res. 50, S423–S428 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  11. H. Yajima, M. Komatsu, T. Schermerhorn, T. Aizawa, T. Kaneko, M. Nagau, G.W. Sharp, K. Hashizume, cAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel-independent pathway of glucose signaling in rat pancreatic islets. Diabetes 48, 1006–1012 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. H. Oshima, M.M. Taketo, M. Oshima, Destruction of pancreatic β-cells by transgenic induction of prostaglandin E2 in the Islets. J. Biol. Chem. 281, 29330–29336 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. K. Song, X. Zhang, C. Zhao, N.T. Ang, Z.A. Ma, Inhibition of Ca2+-independent phospholipase A2 results in insufficient insulin secretion and impaired glucose tolerance. Mol. Endocrinol. 19, 504–515 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. S. Bao, A. Bohrer, S. Ramanadham, W. Jin, S. Zhang, J. Turk, Effects of stable suppression of Group VIA phospholipase A2 expression on phospholipid content and composition, insulin secretion, and proliferation of INS-1 insulinoma cells. J. Biol. Chem. 281, 187–198 (2006)

    Article  CAS  PubMed  Google Scholar 

  15. K. Juhl, M. Hoy, H.L. Olsen, K. Bokvist, A.M. Efanov, E.K. Hoffmann, J. Gromada, cPLA2alpha-evoked formation of arachidonic acid and lysophospholipids is required for exocytosis in mouse pancreatic beta-cells. Am. J. Physiol. Endocrinol. Metab. 285, E73–E81 (2003)

    Article  CAS  PubMed  Google Scholar 

  16. H.M. Milne, C.J. Burns, P.E. Squires, N.D. Evans, J. Pickup, P.M. Jones, S.J. Persaud, Uncoupling of nutrient metabolism from insulin secretion by overexpression of cytosolic phospholipase A(2). Diabetes 54, 116–124 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. P.M. Jones, C.J. Burns, V.D. Belin, H.M. Roderigo-Milne, S.J. Persaud, The role of cytosolic phospholipase A2 in insulin secretion. Diabetes 53, S172–S178 (2005)

    Article  Google Scholar 

  18. S. Ramanadham, Z. Ma, H. Arita, S. Zhang, J. Turk, Type IB secretory phospholipase A2 is contained in insulin secretory granules of pancreatic islet β-cells and is co-secreted with insulin from glucose-stimulated islets. Biochim. Biophys. Acta 1390, 301–312 (1998)

    Article  CAS  PubMed  Google Scholar 

  19. P. Shridas, L. Zahoor, K.J. Forrest, J.D. Layne, N.R. Webb, Group X secretory phospholipase A2 regulates insulin secretion through a cyclooxygenase-2-dependent mechanism. J. Biol. Chem. 289, 27410–27417 (2014)

    Article  CAS  PubMed  PubMed Central  Google 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)

    Article  CAS  PubMed  Google Scholar 

  21. C.R. Wooton-Kee, B.B. Boyanovsky, M.S. Nasser, W.J.S. de Villiers, N.R. Webb, Group V sPLA2 hydrolysis of low-density lipoprotein results in spontaneous particle aggregation and promotes macrophage foam cell formation. Arterioscler. Thromb. Vasc. Biol. 24, 762–767 (2004)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. R. Shoemaker, F. Yiannikouris, S. Thatcher, L. Cassis, ACE2 deficiency reduces beta-cell mass and impairs beta-cell proliferation in obese C57BL/6 mice. Am. J. Physiol. Endocrinol. Metab. 309, E621–E631 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. H. Shinohara, M.A. Balboa, C.A. Johnson, J. Balsinde, E.A. Dennis, Regulation of delayed prostaglandin production in activated P388D1 macrophages by group IV cytosolic and group V secretory phospholipase A2s. J. Biol. Chem. 274, 12263–12268 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Z.X. Meng, J.X. Sun, J.J. Ling, J.H. Lv, D.Y. Zhu, Q. Chen, Y.J. Sun, X. Han, Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction. Diabetologia 49, 2959–2968 (2006)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  Google Scholar 

  27. M. Landt, R.A. Easom, J.R. Colca, B.A. Wolf, J. Turk, L.A. Mills, M.L. McDaniel, Parallel effects of arachidonic acid on insulin secretion, calmodulin-dependent protein kinase activity and protein kinase C activity in pancreatic islets. Cell Calcium 13, 163–172 (1992)

    Article  CAS  PubMed  Google Scholar 

  28. S.A. Metz, Exogenous arachidonic acid promotes insulin release from intact or permeabilized rat islets by dual mechanisms. Putative activation of Ca2+ mobilization and protein kinase C. Diabetes 37, 1453–1469 (1988)

    Article  CAS  PubMed  Google Scholar 

  29. M.A. Balboa, J. Balsinde, M.V. Winstead, J.A. Tischfield, E.A. Dennis, Novel group v phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 macrophages. J. Biol. Chem. 271, 32381–32384 (1996)

    Article  CAS  PubMed  Google Scholar 

  30. E.P. Reaven, G. Gold, W. Walker, G.M. Reaven, Effect of variations in islet size and shape on glucose-stimulated insulin secretion. Horm. Metab. Res. 13, 673–674 (1981)

    Article  CAS  PubMed  Google Scholar 

  31. P.M. Jones, S.J. Persaud, Arachidonic acid as a second messenger in glucose-induced insulin secretion from pancreatic β-cells. J. Endocrinol. 137, 7–14 (1993)

    Article  CAS  PubMed  Google Scholar 

  32. P. Luo, M.H. Wang, Eicosanoids, β-cell function, and diabetes. Prostaglandins Other Lipid Mediat. 95, 1–10 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. S. Ramanadham, A. Bohrer, M. Mueller, P. Jett, R.W. Gross, J. Turk, Mass spectrometric identification and quantitation of arachidonate-containing phospholipids in pancreatic islets: Prominence of plasmenylethanolamine molecular species. Biochemistry 32, 5339–5351 (1993)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  Google Scholar 

  35. E. Valentin, F. Ghomashchi, M.H. Gelb, M. Lazdunski, G. Lambeau, On the diversity of secreted phospholipases A(2). Cloning, tissue distribution, and functional expression of two novel mouse group II enzymes. J. Biol. Chem. 274, 31195–31202 (1999)

    Article  CAS  PubMed  Google Scholar 

  36. S.J. Persaud, D. Muller, V.D. Belin, I. Kitsou-Mylona, H. Asare-Anane, A. Papadimitriou, C.J. Burns, G.C. Huang, S.A. Amiel, P.M. Jones, The role of arachidonic acid and its metabolites in insulin secretion from human Islets of Langerhans. Diabetes 56, 197–203 (2007)

    Article  CAS  PubMed  Google Scholar 

  37. D.A. Jacobson, C.R. Weber, S. Bao, J. Turk, L.H. Philipson, Modulation of the pancreatic islet beta-cell-delayed rectifier potassium channel Kv2.1 by the polyunsaturated fatty acid arachidonate. J. Biol. Chem. 282, 7442–7449 (2007)

    Article  CAS  PubMed  Google Scholar 

  38. D.A. Jacobson, A. Kuznetsov, J.P. Lopez, S. Kash, C.E. Ammala, L.H. Philipson, Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Cell. Metab. 6, 229–235 (2007)

    Article  CAS  PubMed  PubMed Central  Google 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)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  Google Scholar 

  41. Y. Yokota, K. Higashino, K. Nakano, H. Arita, K. Hanasaki, Identification of group X secretory phospholipase A(2) as a natural ligand for mouse phospholipase A(2) receptor. FEBS Lett. 478, 187–191 (2000)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  PubMed Central  Google 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. S. Kamitani, K. Yamada, S. Yamamoto, Y. Ishimoto, T. Ono, A. Saiga, K. Hanasaki, Differences between group x and group v secretory phospholipase A(2) in lipolytic modification of lipoproteins. Cell. Mol. Biol. Lett. 17, 459–478 (2012)

    Article  CAS  PubMed  Google 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Sabire Ozcan, University of Kentucky for providing MIN6 cells and Dr. M. Gelb, University of Washington for supply of anti-mouse GV sPLA2 antibody. We also thank Dr. Wendy Katz for helping us with paraffin embedding and tissue sectioning.

Funding

This work was supported in whole or in part by National Institutes of Health Grant R01 DK082419 (to N. R. W.) and the NIGMS Grant P20 GM103527 (to P. S.).

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Authors and Affiliations

  1. Saha Cardiovascular Research Center, University of Kentucky Medical Center, Lexington, KY, 40536, USA

    Preetha Shridas, Victoria P. Noffsinger, Andrea C. Trumbauer & Nancy R. Webb

  2. Departments of Internal Medicine, University of Kentucky Medical Center, Lexington, KY, 40536, USA

    Preetha Shridas & Victoria P. Noffsinger

  3. Pharmacology and Nutritional Sciences, Division of Nutritional Sciences, University of Kentucky Medical Center, Lexington, KY, 40536, USA

    Nancy R. Webb

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  1. Preetha Shridas
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  2. Victoria P. Noffsinger
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Correspondence to Preetha Shridas.

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The authors declare that they have no competing interests.

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All procedures performed in studies involving mice were in accordance with the guidelines of the University of Kentucky Institutional Animal Care and Use Committees. The article does not contain any studies with human participants performed by any of the authors.

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Shridas, P., Noffsinger, V.P., Trumbauer, A.C. et al. The dual role of group V secretory phospholipase A2 in pancreatic β-cells. Endocrine 58, 47–58 (2017). https://doi.org/10.1007/s12020-017-1379-1

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