Chemical screen to reduce sterol accumulation in Niemann-Pick C disease cells identifies novel lysosomal acid lipase inhibitors

Anton I. Rosenbaum, Madalina Rujoi, Amy Y. Huang, Hong Du, Gregory A. Grabowski, Frederick R. Maxfield

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1155-1165
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1791
Issue number12
DOIs
StatePublished - Sep 17 2009
Externally publishedYes

Keywords

  • Cholesterol accumulation
  • Lysosomal acid lipase
  • Lysosomal storage organelles
  • NPC
  • Orlistat

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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