title: Lysosomal lipid hydrolysis provides substrates for lipid mediator synthesis in murine macrophages.
abstract: Degradation of lysosomal lipids requires lysosomal acid lipase (LAL), the only intracellular lipase known to be active at acidic pH. We found LAL to be expressed in murine immune cells with highest mRNA expression in macrophages and neutrophils. Furthermore, we observed that loss of LAL in mice caused lipid accumulation in white blood cells in the peripheral circulation, which increased in response to an acute inflammatory stimulus. Lal-deficient (-/-) macrophages accumulate neutral lipids, mainly cholesteryl esters, within lysosomes. The cholesteryl ester fraction is particularly enriched in the PUFAs 18:2 and 20:4, important precursor molecules for lipid mediator synthesis. To investigate whether loss of LAL activity affects the generation of lipid mediators and to eliminate potential systemic effects from other cells and tissues involved in the pronounced phenotype of Lal-/- mice, we treated macrophages from Wt mice with the LAL-specific inhibitor LAListat-2. Acute inhibition of LAL resulted in reduced release of 18:2- and 20:4-derived mediators from macrophages, indicating that lipid hydrolysis by LAL is an important source for lipid mediator synthesis in macrophages. We conclude that lysosomes should be considered as organelles that provide precursor molecules for lipid mediators such as eicosanoids.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|Boehringer Ingelheim, Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Korbelius
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Madalina
authors.initials: M
authors.lastname: Duta-Mare
authors.affiliation: 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.
authors.forename: Juliane
authors.initials: J
authors.lastname: Dorow
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rainer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Wegscheider
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Helga
authors.initials: H
authors.lastname: Reicher
authors.affiliation: 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.
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|BioTechMed-Graz, Graz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|BioTechMed-Graz, Graz, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|BioTechMed-Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D006868:Hydrolysis; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis / Q000097:blood; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D002787:Sterol Esterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D002219:Carbamates; D002788:Cholesterol Esters; D015777:Eicosanoids; D008055:Lipids; D013830:Thiadiazoles; C576036:lalistat 2; D002787:Sterol Esterase
keywords: Immune response; Immunity; Immunology and Microbiology Section; LAL-D; eicosanoids; lipid mediator; lysosomal acid lipase; lysosome