title: Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis.
abstract: In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Jandl
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Frei
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujic
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Heimo
authors.initials: H
authors.lastname: Strohmaier
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Juliane
authors.initials: J
authors.lastname: Dorow
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Albert
authors.initials: A
authors.lastname: Wölfler
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dichlberger
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.affiliation: Institutes of *Molecular Biology and Biochemistry and Experimental and Clinical Pharmacology, Center for Medical Research, and Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Molecular Biosciences, University of Graz, Graz, Austria; **Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland dagmar.kratky@medunigraz.at.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D066292:Lipid Droplets / Q000201:enzymology* / Q000473:pathology; D050356:Lipid Metabolism; D052439:Lipid Metabolism Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010538:Peritonitis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000217:Acyltransferases
chemical_list: D008049:Lipase; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: arachidonic acid; eicosanoids; inflammatory cells; lipolysis