| Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. | |
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MedLine Citation:
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PMID: 19965601 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A mutation in NPC1 leads to sequestration of unesterified cholesterol in the late endosomal/lysosomal compartment of every cell culminating in the development of pulmonary, hepatic, and neurodegenerative disease. Acute administration of 2-hydroxypropyl-beta-cyclodextrin (CYCLO) rapidly overcomes this transport defect in both the 7-day-old pup and 49-day-old mature npc1(-/-) mouse, even though this compound is cleared from the body and plasma six times faster in the mature mouse than in the neonatal animal. The liberated cholesterol flows into the cytosolic ester pool, suppresses sterol synthesis, down-regulates SREBP2 and its target genes, and reduces expression of macrophage-associated inflammatory genes. These effects are seen in the liver and brain, as well as in peripheral organs like the spleen and kidney. Only the lung appears to be resistant to these effects. Forty-eight h after CYCLO administration to the 49-day-old animals, fecal acidic, but not neutral, sterol output increases, whole-animal cholesterol burden is reduced, and the hepatic and neurological inflammation is ameliorated. However, lifespan is extended only when the CYCLO is administered to the 7-day-old animals. These studies demonstrate that CYCLO administration acutely reverses the cholesterol transport defect seen in the NPC1 mouse at any age, and this reversal allows the sequestered sterol to be excreted from the body as bile acid. |
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Authors:
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Benny Liu; Charina M Ramirez; Anna M Miller; Joyce J Repa; Stephen D Turley; John M Dietschy |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-11-18 |
Journal Detail:
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Title: Journal of lipid research Volume: 51 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-14 Completed Date: 2010-07-07 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 933-44 Citation Subset: IM |
Affiliation:
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Departments of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Age Factors Animals Bile Acids and Salts / metabolism* Biological Transport / drug effects Cholesterol / metabolism* Feces Female Longevity / drug effects Male Mice Niemann-Pick Disease, Type C / genetics, metabolism Organ Specificity Proteins / genetics, metabolism* beta-Cyclodextrins / administration & dosage, pharmacokinetics, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL09610/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Npc1 protein, mouse; 0/Proteins; 0/beta-Cyclodextrins; 57-88-5/Cholesterol; 94035-02-6/2-hydroxypropyl-beta-cyclodextrin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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