Lysosomal lipid hydrolysis provides substrates for lipid mediator synthesis in murine macrophages

// Stefanie Schlager 1,2 , Nemanja Vujic 1 , Melanie Korbelius 1 , Madalina Duta-Mare 1 , Juliane Dorow 3,4 , Christina Leopold 1 , Silvia Rainer 1 , Martin Wegscheider 1 , Helga Reicher 1 , Uta Ceglarek 3,4 , Wolfgang Sattler 1,5 , Branislav Radovic 1,5 and Dagmar Kratky 1,5 1 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria 2 Boehringer Ingelheim, Vienna, Austria 3 Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany 4 LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany 5 BioTechMed-Graz, Graz, Austria Correspondence to: Dagmar Kratky, email: // Keywords : lysosomal acid lipase, LAL-D, lysosome, eicosanoids, lipid mediator, Immunology and Microbiology Section, Immune response, Immunity Received : December 16, 2016 Accepted : March 19, 2017 Published : March 29, 2017 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.