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Group X secretory phospholipase A2 negatively regulates adipogenesis in murine models.

ABSTRACT: 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 (PPAR?, 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.

SUBMITTER: Li X

PROVIDER: S-EPMC2974424 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Group X secretory phospholipase A2 negatively regulates adipogenesis in murine models.

Li Xia X Shridas Preetha P Forrest Kathy K Bailey William W Webb Nancy R NR

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20100628 11

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 i ...[more]

PMID: 20585029

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Project description:BackgroundPhospholipase A2s mediate the rate-limiting step in the formation of eicosanoids such as cysteinyl leukotrienes (CysLTs). Group IVA cytosolic PLA2α (cPLA2α) is thought to be the dominant PLA2 in eosinophils; however, eosinophils also have secreted PLA2 (sPLA2) activity that has not been fully defined.ObjectivesTo examine the expression of sPLA2 group X (sPLA2-X) in eosinophils, the participation of sPLA2-X in the formation of CysLTs, and the mechanism by which sPLA2-X initiates the synthesis of CysLTs in eosinophils.MethodsPeripheral blood eosinophils were obtained from volunteers with asthma and/or allergy. A rabbit polyclonal anti-sPLA2-X antibody identified sPLA2-X by Western blot. We used confocal microscopy to colocalize the sPLA2-X to intracellular structures. An inhibitor of sPLA2-X (ROC-0929) that does not inhibit other mammalian sPLA2s, as well as inhibitors of the mitogen-activated kinase cascade (MAPK) and cPLA2α, was used to examine the mechanism of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-mediated formation of CysLT.ResultsEosinophils express the mammalian sPLA2-X gene (PLA2G10). The sPLA2-X protein is located in the endoplasmic reticulum, golgi, and granules of eosinophils and moves to the granules and lipid bodies during fMLP-mediated activation. Selective sPLA2-X inhibition attenuated the fMLP-mediated release of arachidonic acid and CysLT formation by eosinophils. Inhibitors of p38, extracellular-signal-regulated kinases 1/2 (p44/42 MAPK), c-Jun N-terminal kinase, and cPLA2α also attenuated the fMLP-mediated formation of CysLT. The sPLA2-X inhibitor reduced the phosphorylation of p38 and extracellular-signal-regulated kinases 1/2 (p44/42 MAPK) as well as cPLA2α during cellular activation, indicating that sPLA2-X is involved in activating the MAPK cascade leading to the formation of CysLT via cPLA2α. We further demonstrate that sPLA2-X is activated before secretion from the cell during activation. Short-term priming with IL-13 and TNF/IL-1β increased the expression of PLA2G10 by eosinophils.ConclusionsThese results demonstrate that sPLA2-X plays a significant role in the formation of CysLTs by human eosinophils. The predominant role of the enzyme is the regulation of MAPK activation that leads to the phosphorylation of cPLA2α. The sPLA2-X protein is regulated by proteolytic cleavage, suggesting that an inflammatory environment may promote the formation of CysLTs through this mechanism. These results have important implications for the treatment of eosinophilic disorders such as asthma.

Dataset Information

Group X secretory phospholipase A2 negatively regulates adipogenesis in murine models.

Publications

Group X secretory phospholipase A2 negatively regulates adipogenesis in murine models.

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