ArticleMolecular metabolism2022
Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases.
Article in Molecular metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia.Leukemia · 2026Article
- Latistat-2 modulates apoptosis and differentiation of human dental pulp stem cells.Odontology · 2026Article
- EBV infection outcomes determined by monocyte and TREG-driven immune dynamics in an ex vivo pbmc model.PLoS pathogens · 2026Article
- EBV INFECTION OUTCOMES DETERMINED BY MONOCYTE AND TbioRxiv : the preprint server for biology · 2025Article
- Lipolysis gone rogue: the HSL connection in feeding cancer.Cell biology and toxicology · 2025Review
- Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.The Journal of clinical investigation · 2025Article
- Cellular Uptake and Trafficking of Lipid Nanocarriers Using High-Resolution Electron Microscopy.AAPS PharmSciTech · 2025Article
- Does Early Diagnosis and Treatment Alter the Clinical Course of Wolman Disease? Divergent Trajectories in Two Siblings and a Consideration for Newborn Screening.International journal of neonatal screening · 2025Article
- Loss or inhibition of lysosomal acid lipaseBBA advances · 2025Article
- From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Article
- The N-degron pathway mediates lipophagy: The chemical modulation of lipophagy in obesity and NAFLD.Metabolism: clinical and experimental · 2023Article
- Recent insights into lysosomal acid lipase deficiency.Trends in molecular medicine · 2023Review
- Dysregulation of Placental Lipid Hydrolysis by High-Fat/High-Cholesterol Feeding and Gestational Diabetes Mellitus in Mice.International journal of molecular sciences · 2022Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
objectivesLysosomal acid lipase (LAL) is the key enzyme, which degrades neutral lipids at an acidic pH in lysosomes. The role of LAL in various cellular processes has mostly been studied in LAL-knockout 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 and Lalistat-2.
methodsWe performed lipid hydrolase activity assays and serine hydrolase-specific activity-based labeling combined with quantitative proteomics to investigate potential off-target effects of Lalistat-1 and -2.
resultsPharmacological LAL inhibition but not genetic loss of LAL impairs isoproterenol-stimulated lipolysis as well as neutral triglyceride and cholesteryl ester hydrolase activities. Apart from LAL, Lalistat-1 and -2 also inhibit major cytosolic lipid hydrolases responsible for lipid degradation in primary cells at neutral pH through off-target effects. Their binding to the active center of the enzymes leads to a decrease in neutral lipid hydrolase activities in cells overexpressing the respective enzymes.
conclusionsOur findings are critically important since they demonstrate that commonly used concentrations of these inhibitors are not suitable to investigate the role of LAL-specific lipolysis in lysosomal function, signaling pathways, and autophagy. The interpretation of their effects on lipid metabolism should be taken with caution and the applied inhibitor concentrations in cell culture studies should not exceed 1 μM.
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