| Chemical screen to reduce sterol accumulation in Niemann-Pick C disease cells identifies novel lysosomal acid lipase inhibitors. | |
| | |
MedLine Citation:
|
PMID: 19699313 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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:
|
Anton I Rosenbaum; Madalina Rujoi; Amy Y Huang; Hong Du; Gregory A Grabowski; Frederick R Maxfield |
Related Documents
:
|
6735073 - Transformation of 4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one into cholesta... 3618263 - The effect of gluten-free diet supplemented with humana-mct on the level of lipid fract... 1323583 - Development of buffer systems for ph control and evaluation of ph effects on fiber dige... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-08-20 |
Journal Detail:
|
Title: Biochimica et biophysica acta Volume: 1791 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2009 Dec |
Date Detail:
|
Created Date: 2009-11-03 Completed Date: 2010-01-06 Revised Date: 2011-09-26 |
Medline Journal Info:
|
Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
|
Languages: eng Pagination: 1155-65 Citation Subset: IM |
Affiliation:
|
Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals CHO Cells Cattle Cricetinae Cricetulus Drug Evaluation, Preclinical Enzyme Inhibitors / analysis*, pharmacology* Humans Lipoprotein Lipase / metabolism Milk / enzymology Mutation / genetics Niemann-Pick Disease, Type C / enzymology*, pathology RNA Interference RNA, Small Interfering / metabolism Reproducibility of Results Small Molecule Libraries / analysis*, pharmacology* Sterol Esterase / antagonists & inhibitors* Sterols / metabolism* Substrate Specificity / drug effects Time Factors |
| Grant Support | |
ID/Acronym/Agency:
|
DK27083/DK/NIDDK NIH HHS; R37 DK027083-28/DK/NIDDK NIH HHS; R37 DK027083-29/DK/NIDDK NIH HHS; R37 DK027083-30/DK/NIDDK NIH HHS; R37 DK027083-31/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Enzyme Inhibitors; 0/RNA, Small Interfering; 0/Small Molecule Libraries; 0/Sterols; EC 3.1.1.13/Sterol Esterase; EC 3.1.1.34/Lipoprotein Lipase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Molecular analyses of Toxoplasma gondii calmodulin-like domain protein kinase isoform 3.
Next Document: Suppression of VLDL secretion by cultured hepatocytes incubated with chylomicron remnants enriched i...