title: Chemical screen to reduce sterol accumulation in Niemann-Pick C disease cells identifies novel lysosomal acid lipase inhibitors.
abstract: Niemann-Pick C disease (NPC) is a lysosomal storage disorder causing abnormal accumulation of unesterified free cholesterol in lysosomal storage organelles. High content phenotypic microscopy chemical screens in both human and hamster NPC-deficient cells have identified several compounds that partially revert the NPC phenotype. Cell biological and biochemical studies show that several of these molecules inhibit lysosomal acid lipase, the enzyme that hydrolyzes LDL-derived triacylglycerol and cholesteryl esters. The effects of reduced lysosomal acid lipase activity in lowering cholesterol accumulation in NPC mutant cells were verified by RNAi-mediated knockdown of lysosomal acid lipase in NPC1-deficient human fibroblasts. This work demonstrates the utility of phenotypic cellular screens as a means to identify molecular targets for altering a complex process such as intracellular cholesterol trafficking and metabolism.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Anton I
authors.initials: AI
authors.lastname: Rosenbaum
authors.forename: Madalina
authors.initials: M
authors.lastname: Rujoi
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
mesh_terms: D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000494:pharmacology*; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism; D008892:Milk / Q000201:enzymology; D009154:Mutation / Q000235:genetics; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013261:Sterols / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D013261:Sterols; D002787:Sterol Esterase; D008071:Lipoprotein Lipase
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