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

Authors
  • Schlager, Stefanie1, 2
  • Vujic, Nemanja1
  • Korbelius, Melanie1
  • Duta-Mare, Madalina1
  • Dorow, Juliane3, 4
  • Leopold, Christina1
  • Rainer, Silvia1
  • Wegscheider, Martin1
  • Reicher, Helga1
  • Ceglarek, Uta3, 4
  • Sattler, Wolfgang1, 5
  • Radovic, Branislav1, 5
  • Kratky, Dagmar1, 5
  • 1 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria. , (Austria)
  • 2 Boehringer Ingelheim, Vienna, Austria. , (Austria)
  • 3 Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. , (Germany)
  • 4 LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. , (Germany)
  • 5 BioTechMed-Graz, Graz, Austria. , (Austria)
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Jun 20, 2017
Volume
8
Issue
25
Pages
40037–40051
Identifiers
DOI: 10.18632/oncotarget.16673
PMID: 28402950
Source
Medline
Keywords
Language
English
License
Unknown

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.

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