Journal
JOURNAL OF LIPID RESEARCH
Volume 53, Issue 11, Pages 2331-2342Publisher
ELSEVIER
DOI: 10.1194/jlr.M028241
Keywords
Niemann-Pick type C; cholesterol balance; lipoprotein profiles; liver; spleen; macrophage; hippocampal neurons; lysosome; inflammation
Categories
Funding
- Ara Parseghian Medical Research Foundation grants
- National Institutes of Health [T32-GM-007062, TL1-DK-081181]
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An injection of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to mice lacking Niemann Pick type C (NPC) protein results in delayed neurodegeneration, decreased inflammation, and prolonged lifespan. Changes in sterol balance observed in Npc1(-/-) mice 24 h after HP-beta-CD administration suggest that HP-beta-CD facilitates the release of accumulated lysosomal cholesterol, the molecular hallmark of this genetic disorder. Current studies were performed to evaluate the time course of HP-beta-CD effects. Within 3 h after HP-beta-CD injection, decreases in cholesterol synthesis rates and increases in cholesteryl ester levels were detected in tissues of Npc1(-/-) mice. The levels of RNAs for target genes of sterol-sensing transcription factors were altered by 6 h in liver, spleen, and ileum. Despite the cholesterol-binding capacity of HP-beta-CD, there was no evidence of increased cholesterol in plasma or urine of treated Npc1(-/-) mice, suggesting that HP-beta-CD does not carry sterol from the lysosome into the bloodstream for ultimate urinary excretion. Similar changes in sterol balance were observed in cultured cells from Npc1(-/-) mice using HP-beta-CD and sulfobutylether-beta-CD, a variant that can interact with sterol but not facilitate its solubilization. Taken together, our results demonstrate that HP-beta-CD works in cells of Npc1(-/-) mice by rapidly liberating lysosomal cholesterol for normal sterol processing within the cytosolic compartment.-Taylor, A. M., B. Liu, Y. Mari, B. Liu, and J. J. Repa. Cyclodextrin mediates rapid changes in lipid balance in Npc1(-/-) mice without carrying cholesterol through the bloodstream. J. Lipid Res. 2012. 53: 2331-2342.
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