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.
Highlights
An injection of 2-hydroxypropyl--cyclodextrin (HP--CD) to mice lacking Niemann Pick type C (NPC) protein results in delayed neurodegeneration, decreased inflammation, and prolonged lifespan
Significant increases in organ weights, tissue total cholesterol content, and cholesterol synthesis rates in Npc1Ϫ/Ϫ mice compared with their wild-type littermates were evident at the outset (0 h) of this study (Fig. 1), which are consistent with previous reports [28]
By 6 h after HP--CD administration, hepatic cholesterol synthesis rates in Npc1Ϫ/Ϫ mice leveled off at a rate of 197 nmol/g/h and remained steady for the duration of the 12 h study (Fig. 1E). This was a reduction of ف80% compared with the initial rate (Npc1Ϫ/Ϫ 0 h, 1,010 nmol/ g/h) in liver and was even less than that measured in Npc1+/+ mice (580 nmol/g/h)
Summary
An injection of 2-hydroxypropyl--cyclodextrin (HP--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--CD administration suggest that HP--CD facilitates the release of accumulated lysosomal cholesterol, the molecular hallmark of this genetic disorder. Within 3 h after HP--CD injection, decreases in cholesterol synthesis rates and increases in cholesteryl ester levels were detected in tissues of Npc1؊/؊ mice. Despite the cholesterol-binding capacity of HP--CD, there was no evidence of increased cholesterol in plasma or urine of treated Npc1؊/؊ mice, suggesting that HP--CD does not carry sterol from the lysosome into the bloodstream for ultimate urinary excretion. Our results demonstrate that HP--CD works in cells of Npc1؊/؊ mice by rapidly liberating lysosomal cholesterol for normal sterol processing within the cytosolic compartment.—Taylor, A. Cyclodextrin mediates rapid changes in lipid balance in Npc1Ϫ/Ϫ mice without carrying cholesterol through the bloodstream.
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