Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1 -Null Cells.

Niemann-Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-beta-CD, HP-gamma-CD, and their homolog 2-hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-beta-CD and HP-gamma-CD, unlike HP-alpha-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-beta-CD and HP-gamma-CD, unlike HP-alpha-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-beta-CD and HP-gamma-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.