Abstract
An injection of 2-hydroxypropyl-β-cyclodextrin (HP-β-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-β-CD administration suggest that HP-β-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-β-CD effects. Within 3 h after HP-β-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-β-CD, there was no evidence of increased cholesterol in plasma or urine of treated Npc1-/- mice, suggesting that HP-β-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-β-CD and sulfobutylether-β-CD, a variant that can interact with sterol but not facilitate its solubilization. Taken together, our results demonstrate that HP-β-CD works in cells of Npc1-/- mice by rapidly liberating lysosomal cholesterol for normal sterol processing within the cytosolic compartment.
Original language | English (US) |
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Pages (from-to) | 2331-2342 |
Number of pages | 12 |
Journal | Journal of lipid research |
Volume | 53 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2012 |
Keywords
- Cholesterol balance
- Hippocampal neurons
- Inflammation
- Lipoprotein profiles
- Liver
- Lysosome
- Macrophage
- Niemann-Pick type C
- Spleen
ASJC Scopus subject areas
- Biochemistry
- Endocrinology
- Cell Biology