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The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages
- Source :
- PLoS ONE, Vol 6, Iss 12, p e29042 (2011), PLoS ONE
- Publication Year :
- 2011
- Publisher :
- Public Library of Science (PLoS), 2011.
-
Abstract
- Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL) in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC) within the endolysosomal network. The measure of cholesterol esters (CE) further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER) was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2), 3-hydroxy-3-methyl-coenzymeA reductase (HMGCoAR), and low-density lipoprotein receptor (LDLR). The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol.
- Subjects :
- Time Factors
Transcription, Genetic
Gene Identification and Analysis
lcsh:Medicine
Biochemistry
Receptor, IGF Type 2
chemistry.chemical_compound
Molecular cell biology
Homeostasis
Enzyme Inhibitors
lcsh:Science
Multidisciplinary
biology
Lipids
Cell biology
Sterols
Cholesterol
HMG-CoA reductase
Androstenes
Membranes and Sorting
lipids (amino acids, peptides, and proteins)
Research Article
Dynamins
Endosome
DNA transcription
Down-Regulation
Endosomes
Endocytosis
Molecular Genetics
Genetics
Humans
Gene Regulation
Biology
Dynamin
Esterification
Macrophages
lcsh:R
Hydrazones
Biological Transport
Cholesterol, LDL
Sterol
chemistry
LDL receptor
biology.protein
lcsh:Q
Gene expression
Gene Function
HeLa Cells
Lipoprotein
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....f4b6e50bcd2d2588d9b8f6fcaa15b468