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PXD030672

PXD030672 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleOff-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases
DescriptionLysosomal acid lipase (LAL) is the key enzyme of lysosomal lipid hydrolysis, which degrades cholesteryl esters (CE), triacylglycerols (TG), diacylglycerols (DG), and retinyl esters. The role of LAL in various cellular processes has mostly been studied in LAL-deficient (Lal-/-) mice, which share phenotypical characteristics with humans suffering from LAL deficiency. In vitro, the cell-specific functions of LAL have been commonly investigated by using the LAL inhibitors Lalistat-1 (L1) and Lalistat-2 (L2). Here, we show that pharmacological LAL inhibition but not genetic loss of LAL impairs isoproterenol-stimulated lipolysis and neutral TG hydrolase (TGH) and CE hydrolase (CEH) activities in mature adipocytes, indicating that L1 and L2 inhibit other lipid hydrolases apart from LAL. Since adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes that degrade cytosolic TG and CE, respectively, at neutral pH, we hypothesized that L1 and L2 also inhibit ATGL and/or HSL through off-target effects. In fact, both inhibitors drastically reduced neutral CEH activity in cells overexpressing mouse and human HSL and neutral TGH activity in cells overexpressing mouse and human ATGL, albeit to a lesser extent. By performing serine hydrolase-specific activity-based labeling in combination with quantitative proteomics, we confirmed that L2 inhibits HSL and other lipid hydrolases, whereas L1 treatment results in less pronounced inhibition of neutral lipid hydrolases. These results demonstrate that commonly used concentrations of L2 (and L1) are not suitable for investigating the role of LAL-specific lipolysis in lysosomal function, signaling pathways, and autophagy.
HostingRepositoryPRIDE
AnnounceDate2022-05-13
AnnouncementXMLSubmission_2022-05-13_07:00:53.106.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSophie Honeder
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListN-ethylmaleimide derivatized cysteine; iodoacetamide derivatized residue
InstrumenttimsTOF Pro
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-12-30 03:51:57ID requested
12022-05-13 07:00:53announced
Publication List
10.1016/J.MOLMET.2022.101510;
Keyword List
submitter keyword: LAL
Lipolysis
Lipid hydrolase activity
ATGL
HSL
MGL
Contact List
Ruth Birner-Gruenberger
contact affiliationResearch and Diagnostic Institute of Pathology, Medical University of Graz, Stiftingtalstrasse 6, 8010 Graz, Austria; Faculty of Technical Chemistry, Institute of Chemical Technologies and Analytics, Technische Universität Wien, Getreidemarkt 9/164, 1060 Vienna, Austria
contact emailruth.birner-gruenberger@tuwien.ac.at
lab head
Sophie Honeder
contact affiliationDiagnostic and Research Institute of Pathology, Medical University of Graz, Stiftingtalstraße 6, 8010 Graz, Austria
contact emailsophie.honeder@medunigraz.at
dataset submitter
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