Lipin-2 Reduces Proinflammatory Signaling Induced by Saturated Fatty Acids in Macrophages

Valdearcos, Martín; Esquinas, Esperanza; Meana, Clara; Peña, Lucía; Gil-de-Gómez, Luis; Balsinde, Jesús; Balboa, Marı́a A.

doi:10.1074/jbc.m112.342915

Cited by 80 publications

(75 citation statements)

References 47 publications

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“…In yeast, DAG pools generated by Pah1 are the major source of DAG for TAG synthesis (Han et al, 2006). Similarly, disruption of the single lipin ortholog in Drosophila melanogaster (Ugrankar et al, 2011) or inactivation of lipin-1 in mice (Mitra et al, 2013) or lipin-2 in human cells (Valdearcos et al, 2012) leads to a decrease in TAG storage. Here, we show that disruption of Arabidopsis PAH1 and PAH2 results in a substantial decrease in TAG content in leaves, suggesting that the role of lipins in TAG synthesis is evolutionarily conserved in plants.…”

Section: Pah1 and Pah2 Play An Evolutionarily Conserved Role In Tag Smentioning

confidence: 99%

Arabidopsis Lipins, PDAT1 Acyltransferase, and SDP1 Triacylglycerol Lipase Synergistically Direct Fatty Acids toward β-Oxidation, Thereby Maintaining Membrane Lipid Homeostasis

et al. 2014

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Triacylglycerol (TAG) metabolism is a key aspect of intracellular lipid homeostasis in yeast and mammals, but its role in vegetative tissues of plants remains poorly defined. We previously reported that PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1 (PDAT1) is crucial for diverting fatty acids (FAs) from membrane lipid synthesis to TAG and thereby protecting against FA-induced cell death in leaves. Here, we show that overexpression of PDAT1 enhances the turnover of FAs in leaf lipids. Using the trigalactosyldiacylglycerol1-1 (tgd1-1) mutant, which displays substantially enhanced PDAT1-mediated TAG synthesis, we demonstrate that disruption of SUGAR-DEPENDENT1 (SDP1) TAG lipase or PEROXISOMAL TRANSPORTER1 (PXA1) severely decreases FA turnover, leading to increases in leaf TAG accumulation, to 9% of dry weight, and in total leaf lipid, by 3-fold. The membrane lipid composition of tgd1-1 sdp1-4 and tgd1-1 pxa1-2 double mutants is altered, and their growth and development are compromised. We also show that two Arabidopsis thaliana lipin homologs provide most of the diacylglycerol for TAG synthesis and that loss of their functions markedly reduces TAG content, but with only minor impact on eukaryotic galactolipid synthesis. Collectively, these results show that Arabidopsis lipins, along with PDAT1 and SDP1, function synergistically in directing FAs toward peroxisomal b-oxidation via TAG intermediates, thereby maintaining membrane lipid homeostasis in leaves.

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Section: Pah1 and Pah2 Play An Evolutionarily Conserved Role In Tag Smentioning

confidence: 99%

Arabidopsis Lipins, PDAT1 Acyltransferase, and SDP1 Triacylglycerol Lipase Synergistically Direct Fatty Acids toward β-Oxidation, Thereby Maintaining Membrane Lipid Homeostasis

et al. 2014

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“…Pools of cells corresponding to five donors were used in all experiments, and replicates were performed with different pools of cells. Macrophage differentiation (95% monocytes) was achieved by incubating the adhered monocytes in RPMI 1640 supplemented with 2 mM L-glutamine, 40 mg/ml gentamicin, and 5% human serum (which contains M-CSF) in a humidified atmosphere with 5% CO 2 , for 2 wk in the absence of exogenous cytokine mixtures, in accordance with previously published procedures (26,(33)(34)(35)(36). To generate classically (M1) or alternatively (M2) activated macrophages, the cells were treated with IFN-g (500 U/ml) plus LPS (10 ng/ml) or IL-4 (1000 U/ml), respectively, in serum-free medium for the indicated periods of time (37,38).…”

Section: Cellsmentioning

confidence: 99%

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Rubio

Rodríguez

Gil-de-Gómez

et al. 2015

The Journal of Immunology

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Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-γ plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-γ plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4–treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4–treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V–derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V–deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4–treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4–treated human macrophages and provide evidence that sPLA2-V–derived LPE is involved in the process.

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“…Human macrophages were obtained from blood monocytes and transfected using the nucleofection technique (Amaxa), as previously described (11,(16)(17)(18).…”

Section: Cellsmentioning

confidence: 99%

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

Meana

Peña

Lordén

et al. 2014

The Journal of Immunology

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Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase involved in the de novo synthesis of phospholipids and triglycerides. Using macrophages from lipin-1–deficient animals and human macrophages deficient in the enzyme, we show in this work that this phosphatase acts as a proinflammatory mediator during TLR signaling and during the development of in vivo inflammatory processes. After TLR4 stimulation lipin-1–deficient macrophages showed a decreased production of diacylglycerol and activation of MAPKs and AP-1. Consequently, the generation of proinflammatory cytokines like IL-6, IL-12, IL-23, or enzymes like inducible NO synthase and cyclooxygenase 2, was reduced. In addition, animals lacking lipin-1 had a faster recovery from endotoxin administration concomitant with a reduced production of harmful molecules in spleen and liver. These findings demonstrate an unanticipated role for lipin-1 as a mediator of macrophage proinflammatory activation and support a critical link between lipid biosynthesis and systemic inflammatory responses.

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Lipin-2 Reduces Proinflammatory Signaling Induced by Saturated Fatty Acids in Macrophages

Cited by 80 publications

References 47 publications

Arabidopsis Lipins, PDAT1 Acyltransferase, and SDP1 Triacylglycerol Lipase Synergistically Direct Fatty Acids toward β-Oxidation, Thereby Maintaining Membrane Lipid Homeostasis

Arabidopsis Lipins, PDAT1 Acyltransferase, and SDP1 Triacylglycerol Lipase Synergistically Direct Fatty Acids toward β-Oxidation, Thereby Maintaining Membrane Lipid Homeostasis

Group V Secreted Phospholipase A2 Is Upregulated by IL-4 in Human Macrophages and Mediates Phagocytosis via Hydrolysis of Ethanolamine Phospholipids

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

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