title: Lipin-1 integrates lipid synthesis with proinflammatory responses during TLR activation in macrophages.
abstract: Lipin-1 is a Mg(2+)-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.
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Meana
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Peña
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Lordén
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Esquinas
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Guijas
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and.
authors.forename: Martín
authors.initials: M
authors.lastname: Valdearcos
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain jbalsinde@ibgm.uva.es mbalboa@ibgm.uva.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
authors.affiliation: Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain jbalsinde@ibgm.uva.es mbalboa@ibgm.uva.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Balboa
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D008055:Lipids; D009687:Nuclear Proteins; D051193:Toll-Like Receptors; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase