Background: Arachidonic acid and its metabolites regulate pancreatic glucose-stimulated insulin secretion (GSIS) through multiple mechanisms. Results: Group X secretory phospholipase A 2 (GX sPLA 2 ) suppresses GSIS; suppression was abolished when COX-2 activity or PGE2-EP3 receptor signaling were inhibited. Conclusion: GX sPLA 2 inhibits GSIS by augmenting PGE2 production. Significance: GX sPLA 2 may be targeted for ameliorating beta cell dysfunction in type 2 diabetes.

Studies in vitro indicate that group X secretory phospholipase A(2) (GX sPLA(2)) potently releases arachidonic acid (AA) and lysophosphatidylcholine from mammalian cell membranes. To define the function of GX sPLA(2) in vivo, our laboratory recently generated C57BL/6 mice with targeted deletion of GX sPLA(2) (GX(-/-) mice). When fed a normal rodent diet, GX(-/-) mice gained significantly more weight and had increased adiposity compared to GX(+/+) mice, which was not attributable to alterations in food consumption or energy expenditure. When treated with adipogenic stimuli ex vivo, stromal vascular cells isolated from adipose tissue of GX(-/-) mice accumulated significantly more (20%) triglyceride compared to cells from GX(+/+) mice. Conversely, overexpression of GX sPLA(2), but not catalytically inactive GX sPLA(2), resulted in a significant 50% reduction in triglyceride accumulation in OP9 adipocytes. The induction of genes encoding adipogenic proteins (PPARγ, SREBP-1c, SCD1, and FAS) was also significantly blunted by 50-80% in OP9 cells overexpressing GX sPLA(2). Activation of the liver X receptor (LXR), a nuclear receptor known to up-regulate adipogenic gene expression, was suppressed in 3T3-L1 and OP9 cells when GX sPLA(2) was overexpressed. Thus, hydrolytic products generated by GX sPLA(2) negatively regulate adipogenesis, possibly by suppressing LXR activation.

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Objective-Abdominal aortic aneurysm (AAA) is a complex vascular disease characterized by matrix degradation and inflammation and is a major cause of mortality in older men. Specific interventions that prevent AAA progression remain to be identified. In this study, we tested the hypothesis that Group X secretory phospholipase A 2 (GX sPLA 2 ), an enzyme implicated in inflammatory processes, mediates AAA.Methods and Results-GX sPLA 2 was detected by immunostaining in human aneurysmal tissue and in angiotensin II (Ang II)-induced AAAs in apolipoprotein E-deficient (apoE −/− ) mice. GX sPLA 2 mRNA was increased significantly (11-fold) in abdominal aortas of apoE −/− mice in response to Ang II infusion. To define the role of GX sPLA 2 in experimental AAAs, apoE −/− and apoE −/− × GX sPLA 2 −/− (GX DKO) mice were infused with Ang II for either 10 (n=7) or 28 (n=24-26) days. Deficiency of GX sPLA 2 significantly reduced the incidence and severity of AAAs, as assessed by ultrasound measurements in vivo of aortic lumens and by computer-assisted morphometric analyses ex vivo of external diameter. Results from gene expression profiling indicated that the expression of specific matrix metalloproteinases and inflammatory mediators was blunted in aortas from GX DKO mice compared to apoE −/− mice after 10-day Ang II infusion. Ang II induction of cyclooxygenase-2, interleukin-6, matrix metalloproteinase (MMP)-2, MMP-13 and MMP-14 was reduced significantly in GX DKO mice compared to apoE −/− mice.

Objective-In vitro data indicate that human LDL modified by Group V secretory phospholipase A 2 (GV sPLA 2 ) is proatherogenic. Consistent with this, gain and loss of function studies demonstrated that GV sPLA 2 promotes atherosclerosis in LDLR Ϫ/Ϫ mice. The current study investigates whether GV sPLA 2 promotes atherosclerotic processes in apoE Ϫ/Ϫ mice. Methods and Results-LDL (dϭ1.019 to 1.063) from apoE Ϫ/Ϫ and LDLR Ϫ/Ϫ mice fed chow or Western diet were hydrolyzed by GV sPLA 2 . Phosphatidylcholine on LDL from LDLR Ϫ/Ϫ mice fed either a chow or Western diet was hydrolyzed to a greater extent (61.1Ϯ0.4% and 45.3Ϯ4.6%) than the corresponding fractions from apoE Ϫ/Ϫ mice (41.7Ϯ3.6% and 39.4Ϯ1.2%). ApoE Ϫ/Ϫ LDL induced macrophage foam cell formation in vitro without modification by GV sPLA 2 , whereas hydrolysis of LDLR Ϫ/Ϫ LDL was a prerequisite for foam cell formation. In contrast to findings in LDLR Ϫ/Ϫ mice, GV sPLA 2 deficiency did not significantly reduce atherosclerosis in apoE Ϫ/Ϫ mice, although collagen content was significantly reduced in lesions of apoE Ϫ/Ϫ mice lacking GV sPLA 2 . Conclusions-The ability of GV sPLA 2 to promote atherosclerotic lipid deposition in apoE Ϫ/Ϫ and LDLR Ϫ/Ϫ mice may be related to its ability to increase the atherogenic potential of LDL from these mice as assessed in vitro. Key Words: sphingomyelin Ⅲ foam cells Ⅲ cholesterol ester Ⅲ atherosclerosis S ecretory phospholipase A 2 (sPLA 2 ) 1 enzymes hydrolyze the fatty acid at the sn-2 position of glycerophospholipids. 1 Ten sPLA 2 isoforms have been described in mammals, and at least 7 of these can be detected in human atherosclerotic lesions. 2 These enzymes have been suggested to promote atherosclerosis through their hydrolyzing activities in the arterial intima. 3-5 GV, GX, and GIII sPLA 2 have been shown to effectively hydrolyze LDL. 6 -9 Our laboratory has shown that GV sPLA 2 hydrolysis of human LDL produces smaller LDL that are susceptible to aggregation, 7 modifications that enhance LDL retention in the vessel wall. In addition, GV sPLA 2 hydrolysis promotes LDL uptake by macrophages through a pathway that is independent of macrophage scavenger receptors and that involves cell surface proteoglycans. 10 Consistent with in vitro findings, overexpression of GV sPLA 2 in bone marrow-derived cells results in increased atherosclerosis in LDLR Ϫ/Ϫ mice, whereas deficiency of the enzyme results in reduced atherosclerosis. 11 However, several considerations led us to question whether GV sPLA 2 plays a major role in atherosclerotic lipid deposition in apoE Ϫ/Ϫ mice. First, in vitro studies have shown that LDL isolated from apoE Ϫ/Ϫ mice are oxidatively modified and hence induce macrophage foam cell formation in a CD36-dependent manner without the requirement for further modification. 12 Secondly, lipoprotein phospholipid (PL) content is altered in apoE Ϫ/Ϫ mice, such that the SM to PC ratio is relatively high because of increased SM production and decreased SM degradation. 13 Because previous in vitro data demonstrate that G...

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