| Improvement in lipid and protein trafficking in Niemann-Pick C1 cells by correction of a secondary enzyme defect. | |
| | |
MedLine Citation:
|
PMID: 20412078 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Different primary lysosomal trafficking defects lead to common alterations in lipid trafficking, suggesting cooperative interactions among lysosomal lipids. However, cellular analysis of the functional consequences of this phenomenon is lacking. As a test case, we studied cells with defective Niemann-Pick C1 (NPC1) protein, a cholesterol trafficking protein whose defect gives rise to lysosomal accumulation of cholesterol and other lipids, leading to NPC disease. NPC1 cells also develop a secondary defect in acid sphingomyelinase (SMase) activity despite a normal acid SMase gene (SMPD1). When acid SMase activity was restored to normal levels in NPC1-deficient CHO cells through SMPD1 transfection, there was a dramatic reduction in lysosomal cholesterol. Two other defects, excess lysosomal bis-(monoacylglycerol) phosphate (BMP) and defective transferrin receptor (TfR) recycling, were also markedly improved. To test its relevance in human cells, the acid SMase activity defect in fibroblasts from NPC1 patients was corrected by SMPD1 transfection or acid SMase enzyme replacement. Both treatments resulted in a dramatic reduction in lysosomal cholesterol. These data show that correcting one aspect of a complex lysosomal lipid storage disease can reduce the cellular consequences even if the primary genetic defect is not corrected. |
| | |
Authors:
|
Cecilia Devlin; Nina H Pipalia; Xianghai Liao; Edward H Schuchman; Frederick R Maxfield; Ira Tabas |
Related Documents
:
|
34438 - An improved method for the isolation and assay of the acid lipase from human liver. 12482628 - Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats. 2108908 - Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial ... 7896308 - Influence of red chilli on lipids and bile acids in different tissues in experimental c... 1685348 - The pharmacological profile of glutamate-evoked ascorbic acid efflux measured by in viv... 16466078 - Gender differences in amino acid use during endurance exercise. |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-02-22 |
Journal Detail:
|
Title: Traffic (Copenhagen, Denmark) Volume: 11 ISSN: 1600-0854 ISO Abbreviation: Traffic Publication Date: 2010 May |
Date Detail:
|
Created Date: 2010-04-23 Completed Date: 2010-07-21 Revised Date: 2011-09-26 |
Medline Journal Info:
|
Nlm Unique ID: 100939340 Medline TA: Traffic Country: Denmark |
Other Details:
|
Languages: eng Pagination: 601-15 Citation Subset: IM |
Affiliation:
|
Department of Medicine, Columbia University, New York, NY 10032, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Antigens, CD CHO Cells Cholesterol / genetics, metabolism Cricetinae Cricetulus Fibroblasts / metabolism Humans Lipids / genetics Lysosomes / genetics, metabolism Niemann-Pick Disease, Type C / genetics, metabolism Niemann-Pick Diseases / genetics*, metabolism* Protein Transport / genetics Proteins / genetics*, metabolism* Receptors, Transferrin / genetics, metabolism Sphingomyelin Phosphodiesterase / genetics, metabolism Transfection |
| Grant Support | |
ID/Acronym/Agency:
|
DK-27083/DK/NIDDK NIH HHS; HL-57560/HL/NHLBI NIH HHS; R01 HL057560-13/HL/NHLBI NIH HHS; R37 DK027083-31S1/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antigens, CD; 0/CD71 antigen; 0/Lipids; 0/Proteins; 0/Receptors, Transferrin; 57-88-5/Cholesterol; EC 3.1.4.12/Sphingomyelin Phosphodiesterase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Allele Name Translation Tool and Update NomenCLature: software tools for the automated translation o...
Next Document: The Human Phenotype Ontology.