Abstract
Cyclodextrins (CDs) have long been used to manipulate cellular cholesterol levels both in vitro and in vivo, but their direct effects at a cellular level are not well characterized. Recently, CDs have garnered much interest because of their ability to clear stored cholesterol from Niemann Pick Type C (NPC) cells and markedly prolong the life of NPC1 disease mice. Here, we investigate the hypothesis that treatment with 2-hydroxypropyl- β-cyclodextrin (HPB-CD) stimulates lysosomal exocytosis in a calcium-enhanced manner. We propose that this exocytosis is the mechanism by which HPB-CD ameliorates the endolysosomal cholesterol storage phenotype in NPC cells. These findings have significant implications for the use of HPB-CD in biochemical assays and data interpretation as well as for their use for the treatment for NPC and other disorders.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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2-Hydroxypropyl-beta-cyclodextrin
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Animals
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Blotting, Western
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Calcium / metabolism*
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Cell Line
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Cell Survival / drug effects
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Cholesterol / metabolism
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Excipients / pharmacology
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Exocytosis / drug effects*
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Exosomes / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Intracellular Signaling Peptides and Proteins
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Lysosomes / metabolism*
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Mice
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Mice, Inbred BALB C
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Microscopy, Fluorescence
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Niemann-Pick C1 Protein
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Proteins / genetics
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Proteins / metabolism
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beta-Cyclodextrins / pharmacology*
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beta-N-Acetylhexosaminidases / metabolism
Substances
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Excipients
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Intracellular Signaling Peptides and Proteins
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Niemann-Pick C1 Protein
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Npc1 protein, mouse
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Proteins
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beta-Cyclodextrins
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Green Fluorescent Proteins
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2-Hydroxypropyl-beta-cyclodextrin
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Cholesterol
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Extracellular Signal-Regulated MAP Kinases
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beta-N-Acetylhexosaminidases
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Calcium