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• W2015967327 abstract "Studies involving pharmacologic or molecular biologic manipulation of Group VIA phospholipase A2 (iPLA2β) activity in pancreatic islets and insulinoma cells suggest that iPLA2β participates in insulin secretion. It has also been suggested that iPLA2β is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels and arachidonate incorporation into phosphatidylcholine (PC). We have generated iPLA2β-null mice by homologous recombination and have reported that they exhibit reduced male fertility and defective motility of spermatozoa. Here we report that pancreatic islets from iPLA2β-null mice have impaired insulin secretory responses to d-glucose and forskolin. Electrospray ionization mass spectrometric analyses indicate that the abundance of arachidonate-containing PC species of islets, brain, and other tissues from iPLA2β-null mice is virtually identical to that of wild-type mice, and no iPLA2β mRNA was observed in any tissue from iPLA2β-null mice at any age. Despite the insulin secretory abnormalities of isolated islets, fasting and fed blood glucose concentrations of iPLA2β-null and wild-type mice are essentially identical under normal circumstances, but iPLA2β-null mice develop more severe hyperglycemia than wild-type mice after administration of multiple low doses of the β-cell toxin streptozotocin, suggesting an impaired islet secretory reserve. A high fat diet also induces more severe glucose intolerance in iPLA2β-null mice than in wild-type mice, but PLA2β-null mice have greater responsiveness to exogenous insulin than do wild-type mice fed a high fat diet. These and previous findings thus indicate that iPLA2β-null mice exhibit phenotypic abnormalities in pancreatic islets in addition to testes and macrophages. Studies involving pharmacologic or molecular biologic manipulation of Group VIA phospholipase A2 (iPLA2β) activity in pancreatic islets and insulinoma cells suggest that iPLA2β participates in insulin secretion. It has also been suggested that iPLA2β is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels and arachidonate incorporation into phosphatidylcholine (PC). We have generated iPLA2β-null mice by homologous recombination and have reported that they exhibit reduced male fertility and defective motility of spermatozoa. Here we report that pancreatic islets from iPLA2β-null mice have impaired insulin secretory responses to d-glucose and forskolin. Electrospray ionization mass spectrometric analyses indicate that the abundance of arachidonate-containing PC species of islets, brain, and other tissues from iPLA2β-null mice is virtually identical to that of wild-type mice, and no iPLA2β mRNA was observed in any tissue from iPLA2β-null mice at any age. Despite the insulin secretory abnormalities of isolated islets, fasting and fed blood glucose concentrations of iPLA2β-null and wild-type mice are essentially identical under normal circumstances, but iPLA2β-null mice develop more severe hyperglycemia than wild-type mice after administration of multiple low doses of the β-cell toxin streptozotocin, suggesting an impaired islet secretory reserve. A high fat diet also induces more severe glucose intolerance in iPLA2β-null mice than in wild-type mice, but PLA2β-null mice have greater responsiveness to exogenous insulin than do wild-type mice fed a high fat diet. These and previous findings thus indicate that iPLA2β-null mice exhibit phenotypic abnormalities in pancreatic islets in addition to testes and macrophages. Phospholipases A2 (PLA2) 2The abbreviations used are: PLA2, phospholipase A2; BEL, bromoenol lactone suicide substrate; CAD, collisionally activated dissociation; ESI, electrospray ionization; GPC, glycerophosphocholine; HBSS, Hank's balanced salt solution; iPLA2β, Group VIA phospholipase A2; LPC, lysophosphatidylcholine; MS, mass spectrometry; MS/MS, tandem mass spectrometry; PAF, platelet-activating factor; PAPH, phosphatidate phosphohydrolase; PC, phosphatidylcholine; PM, plasma membrane; RT, reverse transcriptase; siRNA, small interfering RNA; SOC, store operated channel; TLC, thin layer chromatography; VOCC, voltage-operated Ca2+ channel; WT, wild type; KO, knock-out; au, area units; CT, CTP:phosphocholine cytidylyltransferase. 2The abbreviations used are: PLA2, phospholipase A2; BEL, bromoenol lactone suicide substrate; CAD, collisionally activated dissociation; ESI, electrospray ionization; GPC, glycerophosphocholine; HBSS, Hank's balanced salt solution; iPLA2β, Group VIA phospholipase A2; LPC, lysophosphatidylcholine; MS, mass spectrometry; MS/MS, tandem mass spectrometry; PAF, platelet-activating factor; PAPH, phosphatidate phosphohydrolase; PC, phosphatidylcholine; PM, plasma membrane; RT, reverse transcriptase; siRNA, small interfering RNA; SOC, store operated channel; TLC, thin layer chromatography; VOCC, voltage-operated Ca2+ channel; WT, wild type; KO, knock-out; au, area units; CT, CTP:phosphocholine cytidylyltransferase. catalyze hydrolysis of the sn-2 fatty acid substituent from glycerophospholipid substrates to yield a free fatty acid, e.g. arachidonic acid, and a 2-lysophospholipid (1Six D.A. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1157) Google Scholar, 2Ma Z. Turk J. Prog. Nucleic Acids Res. Mol. Biol. 2001; 67: 1-33Crossref PubMed Google Scholar) that have intrinsic mediator functions (3Brash A.R. J. Clin. Investig. 2001; 107: 1339-1345Crossref PubMed Google Scholar, 4Radu C.G. Yang L.V. Riedinger M. Au M. Witte O.N. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 245-250Crossref PubMed Scopus (145) Google Scholar) and can initiate synthesis of other mediators (5Murphy R.C. Sala A. Methods Enzymol. 1990; 187: 90-98Crossref PubMed Google Scholar). Arachidonic acid, for example, is converted to prostaglandins, leukotrienes, and epoxytrienes, and acetylation of 2-lysoplasmanylcholine yields platelet-activating factor (PAF) (5Murphy R.C. Sala A. Methods Enzymol. 1990; 187: 90-98Crossref PubMed Google Scholar).Of mammalian PLA2s so far cloned, the PAF-acetylhydrolase PLA2 family exhibits substrate specificity for PAF and oxidized phospholipids, and secretory PLA2 (sPLA2) are low molecular weight enzymes that require mm [Ca2+] for catalysis and affect inflammation and other processes (1Six D.A. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1157) Google Scholar). Of Group IV cytosolic PLA2 (cPLA2) family members (1Six D.A. Dennis E.A. Biochim. Biophys. Acta. 2000; 1488: 1-19Crossref PubMed Scopus (1157) Google Scholar), cPLA2α was the first identified and prefers substrates with sn-2 arachidonoyl residues, catalyzes arachidonate release for subsequent metabolism, associates with its substrates in membranes when cytosolic [Ca2+], rises, and is also regulated by phosphorylation (6Gijon M.A. Spencer D.M. Kaiser A.L. Leslie C.C. J. Cell Biol. 1999; 145: 1219-1232Crossref PubMed Scopus (178) Google Scholar). There are additional members of the cPLA2 family encoded by separate genes (7Underwood K.W. Song C. Kriz R.W. Chang X.J. Knopf J.L. Lin L.-L. J. Biol. Chem. 1998; 273: 21926-21932Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 8Pickard R.T. Strifler B.A. Kramer R.M. Sharp J.D. J. Biol. Chem. 1999; 274: 8823-8831Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 9Song C. Chang X.J. Bean K.M. Proia M.S. Knopf J.L. Kriz R.W. J. Biol. Chem. 1999; 274: 17063-17067Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 10Ohto T. Uozumi N. Hirabayashi T. Shimizu T. J. Biol. Chem. 2005; 280: 24576-24583Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar).The Group VI PLA2 (iPLA2) enzymes (11Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 12Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 13Ma Z. Ramanadham S. Kempe K. Chi X.S. Ladenson J. Turk J. J. Biol. Chem. 1997; 272: 11118-11127Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) do not require Ca2+ for catalysis and are inhibited by a bromoenol lactone (BEL) suicide substrate (14Hazen S.L. Zupan L.A. Weiss R.H. Getman D.P. Gross R.W. J. Biol. Chem. 1991; 266: 7227-7232Abstract Full Text PDF PubMed Google Scholar) that does not inhibit sPLA2 or cPLA2 at similar concentrations (14Hazen S.L. Zupan L.A. Weiss R.H. Getman D.P. Gross R.W. J. Biol. Chem. 1991; 266: 7227-7232Abstract Full Text PDF PubMed Google Scholar, 15Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 16Ma Z. Ramanadham S. Hu Z. Turk J. Biochim. Biophys. Acta. 1998; 1391: 384-400Crossref PubMed Scopus (42) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). The Group VIA PLA2 (iPLA2β) resides in the cytoplasm of resting cells, but Group VIB PLA2 (iPLA2γ) contains a peroxisomal targeting sequence and is membrane-associated (18Mancuso D.J. Jenkins C.M. Gross R.W. J. Biol. Chem. 2000; 275: 9937-9945Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 19Tanaka H. Takeya R. Sumimoto H. Biochem. Biophys. Res. Commun. 2000; 272: 320-326Crossref PubMed Scopus (75) Google Scholar). These enzymes belong to a larger class of serine lipases that are encoded by multiple genes (20van Tienhoven M. Atkins J. Li Y. Glynn P. J. Biol. Chem. 2002; 277: 20942-20948Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 21Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). The iPLA2β enzymes cloned from various species are 84–88 kDa proteins that contain a GXSXG lipase consensus sequence and eight stretches of a repetitive motif homologous to that in the protein binding domain of ankyrin (11Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 12Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 13Ma Z. Ramanadham S. Kempe K. Chi X.S. Ladenson J. Turk J. J. Biol. Chem. 1997; 272: 11118-11127Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar).It has been proposed that iPLA2β plays housekeeping roles in phospholipid metabolism (22Balsinde J. Biochem. J. 2002; 364: 695-702Crossref PubMed Scopus (70) Google Scholar, 23Balsinde J. Balboa M.A. Cell Signal. 2005; 17: 1052-1062Crossref PubMed Scopus (169) Google Scholar), such as generating lysophospholipid acceptors for incorporating arachidonic acid into phosphatidylcholine (PC) of murine P388D1 macrophage-like cells, based on studies involving reducing iPLA2 activity with BEL or an antisense oligonucleotide that suppresses [3H]arachidonate incorporation into PC and reduces [3H]lysophosphatidylcholine (LPC) levels (23Balsinde J. Balboa M.A. Cell Signal. 2005; 17: 1052-1062Crossref PubMed Scopus (169) Google Scholar, 24Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (251) Google Scholar, 25Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Arachidonate incorporation involves a deacylation/reacylation cycle of phospholipid remodeling (26Lands W.E.M. Crawford C.G. The Enzymes of Biological Membranes. Plenum Press, New York1997Google Scholar, 27Chilton F.H. Fonteh A.N. Surette M.E. Triggiani M. Winkler J.D. Biochim. Biophys. Acta. 1996; 1299: 1-15Crossref PubMed Scopus (199) Google Scholar), and the level of LPC is thought to limit the [3H]arachidonic acid incorporation rate into P388D1 cell PC (24Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (251) Google Scholar, 25Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar).Another housekeeping function for iPLA2β in PC homeostasis has been proposed from studies of overexpression of CTP: phosphocholine cytidylyltransferase (CT) (28Baburina I. Jackowski S. J. Biol. Chem. 1999; 274: 9400-9408Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 29Barbour S.E. Kapur A. Deal C.L. Biochim. Biophys. Acta. 1999; 1439: 77-88Crossref PubMed Scopus (72) Google Scholar), which catalyzes the rate-limiting step in PC synthesis. Cells that overexpress CT exhibit increased rates of PC biosynthesis and degradation and little net change in PC levels, suggesting that PC degradation is up-regulated to prevent excess PC accumulation. Increased PC degradation in CT-overexpressing cells is prevented by BEL, and iPLA2β protein and activity increase, suggesting that iPLA2β is up-regulated (28Baburina I. Jackowski S. J. Biol. Chem. 1999; 274: 9400-9408Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 29Barbour S.E. Kapur A. Deal C.L. Biochim. Biophys. Acta. 1999; 1439: 77-88Crossref PubMed Scopus (72) Google Scholar).Many other iPLA2β functions have been proposed (30Akiba S. Mizunaga S. Kume K. Hayama M. Sato T. J. Biol. Chem. 1999; 274: 19906-19912Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 31Atsumi G. Murakami M. Kojima K. Hadano A. Tajima M. Kudo I. J. Biol. Chem. 2000; 275: 18248-18258Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 32Jenkins C.M. Han X. Mancuso D.J. Gross R.W. J. Biol. Chem. 2002; 277: 32807-32814Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 33Seegers H.C. Gross R.W. Boyle W.A. J. Pharmacol. Exp. Ther. 2002; 302: 918-923Crossref PubMed Scopus (23) Google Scholar, 34Perez R. Melero R. Balboa M.A. Balsinde J. J. Biol. Chem. 2004; 279: 40385-40391Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 35Yellaturu C.R. Rao G.N. J. Biol. Chem. 2003; 278: 43831-43837Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 36Smani T. Zakharov S.I. Csutora P. Leno E. Trepakova E.S. Bolotina V.M. Nat. Cell Biol. 2004; 6: 113-120Crossref PubMed Scopus (230) Google Scholar, 37Martinson B.D. Albert C.J. Corbett J.A. Wysolmerski R.B. Ford D.A. J. Lipid Res. 2003; 44: 1686-1691Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 38Moran J.M. Buller R.M. McHowat J. Turk J. Wohltmann M. Gross R.W. Corbett J.A. J. Biol. Chem. 2005; 280: 28162-28168Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 39Guo Z. Su W. Ma Z. Smith G.M. Gong M.C. J. Biol. Chem. 2003; 278: 1856-1863Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 40Balboa M.A. Saez Y. Balsinde J. J. Immunol. 2003; 170: 5276-5280Crossref PubMed Scopus (54) Google Scholar, 41Song K. Zhang X. Zhao C. Ang N.T. Ma Z.A. Mol. Endocrinol. 2005; 19: 504-515Crossref PubMed Scopus (45) Google Scholar, 42Larsson Forsell P.K. Kennedy B.P. Claesson H.E. Eur. J. Biochem. 1999; 262: 575-585Crossref PubMed Scopus (111) Google Scholar, 43Ma Z. Wang X. Nowatzke W. Ramanadham S. Turk J. J. Biol. 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Proposed functions include signaling in secretion (40Balboa M.A. Saez Y. Balsinde J. J. Immunol. 2003; 170: 5276-5280Crossref PubMed Scopus (54) Google Scholar, 41Song K. Zhang X. Zhao C. Ang N.T. Ma Z.A. Mol. Endocrinol. 2005; 19: 504-515Crossref PubMed Scopus (45) Google Scholar, 45Owada S. Larsson O. Arkhammar P. Katz A.I. Chibalin A.V. Berggren P.O. Bertorello A.M. J. Biol. Chem. 1999; 274: 2000-2008Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 46Simonsson E. Ahren B. Int. J. Pancreatol. 2000; 27: 1-11Crossref PubMed Google Scholar, 47Ramanadham S. Gross R.W. Han X. Turk J. Biochemistry. 1993; 32: 337-346Crossref PubMed Google Scholar, 48Ramanadham S. Wolf M.J. Jett P.A. Gross R.W. Turk J. Biochemistry. 1994; 33: 7442-7452Crossref PubMed Google Scholar, 49Ramanadham S. Wolf M.J. Li B. Bohrer A. Turk J. Biochim. Biophys. Acta. 1997; 1344: 153-164Crossref PubMed Scopus (33) Google Scholar, 50Ramanadham S. Song H. Hsu F.F. Zhang S. Crankshaw M. Grant G.A. Newgard C.B. Bao S. Ma Z. Turk J. Biochemistry. 2003; 42: 13929-13940Crossref PubMed Scopus (35) Google Scholar), and BEL attenuates glucose-induced insulin secretion, arachidonate release, and rises in cytosolic [Ca2+] in pancreatic islet β-cells and insulinoma cells (41Song K. Zhang X. Zhao C. Ang N.T. Ma Z.A. Mol. Endocrinol. 2005; 19: 504-515Crossref PubMed Scopus (45) Google Scholar, 45Owada S. Larsson O. Arkhammar P. Katz A.I. Chibalin A.V. Berggren P.O. Bertorello A.M. J. Biol. Chem. 1999; 274: 2000-2008Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 46Simonsson E. Ahren B. Int. J. Pancreatol. 2000; 27: 1-11Crossref PubMed Google Scholar, 47Ramanadham S. Gross R.W. Han X. Turk J. Biochemistry. 1993; 32: 337-346Crossref PubMed Google Scholar, 48Ramanadham S. Wolf M.J. Jett P.A. Gross R.W. Turk J. Biochemistry. 1994; 33: 7442-7452Crossref PubMed Google Scholar, 49Ramanadham S. Wolf M.J. Li B. Bohrer A. Turk J. Biochim. Biophys. Acta. 1997; 1344: 153-164Crossref PubMed Scopus (33) Google Scholar, 50Ramanadham S. Song H. Hsu F.F. Zhang S. Crankshaw M. Grant G.A. Newgard C.B. Bao S. Ma Z. Turk J. Biochemistry. 2003; 42: 13929-13940Crossref PubMed Scopus (35) Google Scholar).Many cells, including β-cells, express multiple distinct PLA2 (13Ma Z. Ramanadham S. Kempe K. Chi X.S. Ladenson J. Turk J. J. Biol. Chem. 1997; 272: 11118-11127Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 16Ma Z. Ramanadham S. Hu Z. Turk J. Biochim. Biophys. Acta. 1998; 1391: 384-400Crossref PubMed Scopus (42) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 51Ramanadham S. Ma Z. Arita H. Zhang S. Turk J. Biochim. Biophys. Acta. 1998; 1390: 301-312Crossref PubMed Scopus (33) Google Scholar, 52Su X. Mancuso D.J. Bickel P.E. Jenkins C.M. Gross R.W. J. Biol. Chem. 2004; 279: 21740-21748Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 53Shirai Y. Balsinde J. Dennis E.A. Biochim. Biophys. Acta. 2005; 1735: 119-129Crossref PubMed Scopus (0) Google Scholar), which might reflect redundancy or specific functions of individual PLA2. The mechanism-based iPLA2 inhibitor BEL and its enantiomers inhibit iPLA2 at concentrations lower than those required to inhibit sPLA2 or cPLA2 (14Hazen S.L. Zupan L.A. Weiss R.H. Getman D.P. Gross R.W. J. Biol. Chem. 1991; 266: 7227-7232Abstract Full Text PDF PubMed Google Scholar, 15Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 16Ma Z. Ramanadham S. Hu Z. Turk J. Biochim. Biophys. Acta. 1998; 1391: 384-400Crossref PubMed Scopus (42) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 32Jenkins C.M. Han X. Mancuso D.J. Gross R.W. J. Biol. Chem. 2002; 277: 32807-32814Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar), and this has been widely exploited to discern potential biological roles for iPLA2 (30Akiba S. Mizunaga S. Kume K. Hayama M. Sato T. J. Biol. Chem. 1999; 274: 19906-19912Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 31Atsumi G. Murakami M. Kojima K. Hadano A. Tajima M. Kudo I. J. Biol. Chem. 2000; 275: 18248-18258Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 32Jenkins C.M. Han X. Mancuso D.J. Gross R.W. J. Biol. Chem. 2002; 277: 32807-32814Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 33Seegers H.C. Gross R.W. Boyle W.A. J. Pharmacol. Exp. Ther. 2002; 302: 918-923Crossref PubMed Scopus (23) Google Scholar, 34Perez R. Melero R. Balboa M.A. Balsinde J. J. Biol. Chem. 2004; 279: 40385-40391Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 35Yellaturu C.R. Rao G.N. J. Biol. Chem. 2003; 278: 43831-43837Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 36Smani T. Zakharov S.I. Csutora P. Leno E. Trepakova E.S. Bolotina V.M. Nat. Cell Biol. 2004; 6: 113-120Crossref PubMed Scopus (230) Google Scholar, 37Martinson B.D. Albert C.J. Corbett J.A. Wysolmerski R.B. Ford D.A. J. Lipid Res. 2003; 44: 1686-1691Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 38Moran J.M. Buller R.M. McHowat J. Turk J. Wohltmann M. Gross R.W. Corbett J.A. J. Biol. Chem. 2005; 280: 28162-28168Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 39Guo Z. Su W. Ma Z. Smith G.M. Gong M.C. J. Biol. Chem. 2003; 278: 1856-1863Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 40Balboa M.A. Saez Y. Balsinde J. J. Immunol. 2003; 170: 5276-5280Crossref PubMed Scopus (54) Google Scholar, 54Akiba S. Sato T. Biol. Pharm. Bull. 2004; 27: 1174-1178Crossref PubMed Scopus (105) Google Scholar, 55Larsson Forsell P.K. Runarsson G. Ibrahim M. Bjorkholm M. Claesson H.E. FEBS Lett. 1998; 434: 295-299Crossref PubMed Scopus (34) Google Scholar, 56Murakami M. Kambe T. Shimbara S. Kudo I. J. Biol. Chem. 1999; 274: 3103-3115Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). BEL also inhibits enzymes other than iPLA2β; however, including serine proteases (57Daniels S. Cooney E. Sofia M. Chakravarty P. Katzenellenbogen J. J. Biol. Chem. 1983; 258: 15046-15053Abstract Full Text PDF PubMed Google Scholar) and phosphatidate phosphohydrolase-1 (PAPH-1) (58Fuentes L. Perez R. Nieto M.L. Balsinde J. Balboa M.A. J. Biol. Chem. 2003; 278: 44683-44690Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), which accounts for some of its biological effects. In addition, BEL inhibits iPLA2γ (18Mancuso D.J. Jenkins C.M. Gross R.W. J. Biol. Chem. 2000; 275: 9937-9945Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar) and at least four other serine lipases (20van Tienhoven M. Atkins J. Li Y. Glynn P. J. Biol. Chem. 2002; 277: 20942-20948Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 21Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar).The ambiguity of pharmacologic studies with BEL makes manipulating iPLA2β expression by molecular biologic means an attractive alternative to study iPLA2β functions, and physiological roles for PLA2s can be studied with genetic gain- or loss-of-function manipulations. Stably transfected INS-1 insulinoma cells that overexpress iPLA2β exhibit amplified insulin secretory responses to glucose, particularly in the presence of agents that elevate cAMP (59Ma Z. Ramanadham S. Wohltmann M. Bohrer A. Hsu F.F. Turk J. J. Biol. Chem. 2001; 276: 13198-13208Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), and stable suppression of PLA2β expression in transfected insulinoma cells that express small interfering RNA (siRNA) directed against iPLA2β mRNA results in impaired insulin secretory responses to those stimuli (60Bao S. Bohrer A. Ramanadham S. Jin W. Zhang S. Turk J. J. Biol. Chem. 2006; 281: 187-198Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar).Although these observations support pharmacologic evidence that iPLA2β participates in signaling or effector events involved in insulin secretion (45Owada S. Larsson O. Arkhammar P. Katz A.I. Chibalin A.V. Berggren P.O. Bertorello A.M. J. Biol. Chem. 1999; 274: 2000-2008Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 46Simonsson E. Ahren B. Int. J. Pancreatol. 2000; 27: 1-11Crossref PubMed Google Scholar, 47Ramanadham S. Gross R.W. Han X. Turk J. Biochemistry. 1993; 32: 337-346Crossref PubMed Google Scholar, 48Ramanadham S. Wolf M.J. Jett P.A. Gross R.W. Turk J. Biochemistry. 1994; 33: 7442-7452Crossref PubMed Google Scholar, 49Ramanadham S. Wolf M.J. Li B. Bohrer A. Turk J. Biochim. Biophys. Acta. 1997; 1344: 153-164Crossref PubMed Scopus (33) Google Scholar, 50Ramanadham S. Song H. Hsu F.F. Zhang S. Crankshaw M. Grant G.A. Newgard C.B. Bao S. Ma Z. Turk J. Biochemistry. 2003; 42: 13929-13940Crossref PubMed Scopus (35) Google Scholar, 51Ramanadham S. Ma Z. Arita H. Zhang S. Turk J. Biochim. Biophys. Acta. 1998; 1390: 301-312Crossref PubMed Scopus (33) Google Scholar), genetic manipulations at the level of the whole organism sometimes provide information about physiological role(s) of specific gene products that are not readily apparent from results of experiments with cultured cells. Disruption of the gene encoding the Kir6.2 potassium channel, for example, prevents the rise in intracellular [Ca2+] ordinarily induced by d-glucose in pancreatic islet β-cells and suppresses glucose-induced insulin secretion, but, contrary to expectations, non-obese Kir6.2-null mice do not exhibit hyperglycemia because of a counterbalancing increase in insulin action (61Miki T. Nagashima K. Tashiro F. Kotake K. Yoshitomi H. Tamamoto A. Gonoi T. Iwanaga T. Myazaki J. Seino S. Proc. Natl. Acad. Sci. 1998; 95: 10402-10496Crossref PubMed Scopus (0) Google Scholar), although glucose intolerance can be induced in these mice by dietary interventions and obesity (62Seino S. Iwanaga T. Nagashima K. Miki T. Diabetes. 2000; 49: 311-318Crossref PubMed Google Scholar, 63Remedi M.S. Koster J.C. Markova K. Seino S. Miki T. Patton B.L. McDaniel M.L. Nichols C.G. Diabetes. 2000; 53: 3159-3167Crossref Scopus (31) Google Scholar).Disruption of the gene encoding cPLA2α by homologous recombination to yield cPLA2α-null mice has revealed a role for that enzyme in parturition, allergic responses, and post-ischemic brain injury (64Bonventre J.V. Huang Z. Taheri M.R. O'Leary E. Li E. Moskowitz M.A. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (730) Google Scholar, 65Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (614) Google Scholar), and we have generated iPLA2β-null mice by similar methods in order to examine the physiological functions of iPLA2β (66Bao S. Miller D.J. Ma Z. Wohltmann M. Eng G. Ramanadham S. Moley K. Turk J. J. Biol. Chem. 2004; 279: 38194-38200Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Among various tissues, testes of wild-type mice express the highest iPLA2β levels, and male iPLA2β–/– mice produce spermatozoa with reduced motility and impaired ability to fertilize mouse oocytes. Male iPLA2β–/– mice are much less fertile than wild-type males, but female iPLA2β–/– mouse fertility is not impaired (66Bao S. Miller D.J. Ma Z. Wohltmann M. Eng G. Ramanadham S. Moley K. Turk J. J. Biol. Chem. 2004; 279: 38194-38200Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar).In this report, we examine the insulin secretory responses and phospholipid composition of pancreatic islets isolated from iPLA2β-null mice and their wild-type littermates and the effects on glucose homeostasis of metabolic stresses that include administration of multiple low doses of the β-cell toxin streptozotocin and prolonged feeding of a diet with a high fat content.EXPERIMENTAL PROCEDURESMaterials—BEL [(E)-6-(bromo-methylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one] was obtained from Cayman Chemical (Ann Arbor, MI); enhanced chemiluminescence (ECL) reagents from Amersham Biosciences; standard phospholipids including 1,2-dimyristoyl-sn-glycerophosphocholine (14:0/14:0-GPC) and 18:0/22:6-GPC from Avanti Polar Lipids (Birmingham, AL); SDS-PAGE supplies from Bio-Rad; organic solvents from Fisher Scientific; Coomassie reagent from Pierce; streptozotocin, ATP, ampicillin, kanamycin, common reagents, and salts from Sigma; culture media, penicillin, streptomycin, Hanks' balanced salt solution (HBSS), l-glutamine, agarose, molecular mass standards, and RT-PCR reagents from Invitrogen (Carlsbad, CA); fetal bovine serum from Hyclone (Logan UT); Pentex bovine serum albumin (BSA, fatty acid free, fraction V) from ICN Biomedical (Aurora, OH); and forskolin from Calbiochem (La Jolla, CA). Krebs-Ringer bicarbonate buffer (KRB) contained 25 mm HEPES (pH 7.4), 115 mm NaCl, 24 mm NaHCO3, 5 mm KCl, 1 mm MgCl2, and 2.5 mm CaCl2.Generating iPLA –/–2 Knock-out Mice—The Washington University Animal Studies Committee approved all studies described here and elsewhere in this article. The knock-out construct was prepared with a P1 clone containing an iPLA2β gene fragment obtained from screening a 129/SvJ mouse genomic DNA library with rat iPLA2β cDNA (66Bao S. Miller D.J. Ma" @default.
• W2015967327 created "2016-06-24" @default.
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• W2015967327 date "2006-07-01" @default.
• W2015967327 modified "2023-09-26" @default.
• W2015967327 title "Insulin Secretory Responses and Phospholipid Composition of Pancreatic Islets from Mice That Do Not Express Group VIA Phospholipase A2 and Effects of Metabolic Stress on Glucose Homeostasis" @default.
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