Journal
CYTOMETRY PART A
Volume 77A, Issue 8, Pages 751-760Publisher
WILEY
DOI: 10.1002/cyto.a.20911
Keywords
phagosome; high throughput cell-based screen; lipase; hydrolase inhibitor; lysosomal acid lipase; endosomal lipase; lipid homeostasis
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Funding
- National Institutes of Health [AI057086, AI080651]
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Macrophages play a central role in tissue homeostasis and the immune system. Their primary function is to internalize cellular debris and microorganisms for degradation within their phagosomes. In this context, their capacity to process and sequester lipids such as triacylglycerides and cholesteryl esters makes them key players in circulatory diseases, such as atheroclerosis. To discover new inhibitors of lipolytic processing within the phagosomal system of the macrophage, we have developed a novel, cell-based assay suitable for high-throughput screening. We employed particles carrying a fluorogenic triglyceride substrate and a calibration fluor to screen for inhibitors of phagosomal lipolysis. A panel of secondary assays were employed to discriminate between lipase inhibitors and compounds that perturbed general phagosomal trafficking events. This process enabled us to identify a new structural class of pyrazole-methanone compounds that directly inhibit lysosomal and lipoprotein lipase activity. (C) 2010 International Society for Advancement of Cytometry
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