PXD030672-1

PXD030672 is an original dataset announced via ProteomeXchange.

Title	Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases
Description	Lysosomal 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.
HostingRepository	PRIDE
AnnounceDate	2022-05-13
AnnouncementXML	Submission_2022-05-13_07:00:53.106.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sophie Honeder
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	N-ethylmaleimide derivatized cysteine; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-30 03:51:57	ID requested
⏵ 1	2022-05-13 07:00:53	announced
2	2023-11-14 08:54:28	announced	2023-11-14: Updated project metadata.

10.1016/J.MOLMET.2022.101510;

submitter keyword: LAL

Lipolysis

Lipid hydrolase activity

ATGL

HSL

MGL

Ruth Birner-Gruenberger
contact affiliation	Research 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 email	ruth.birner-gruenberger@tuwien.ac.at
lab head
Sophie Honeder
contact affiliation	Diagnostic and Research Institute of Pathology, Medical University of Graz, Stiftingtalstraße 6, 8010 Graz, Austria
contact email	sophie.honeder@medunigraz.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/05/PXD030672

PRIDE project URI

• PRIDE
  1. PXD030672
     1. Label: PRIDE project
     2. Name: Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases