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.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9077, USA.
Anna M
AM
Taylor
Bing
B
Liu
Yelenis
Y
Mari
Benny
B
Liu
Joyce J
JJ
Repa
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism* / Q000652:urine; D016207:Cytokines / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism / Q000187:drug effects*; D008074:Lipoproteins / Q000097:blood; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000378:metabolism / Q000652:urine; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology*
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin; D002784:Cholesterol