Cyclodextrin mediates rapid changes in lipid balance in Npc1-/- mice without carrying cholesterol through the bloodstream.

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.