Departments of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151, USA.
J Lipid Res. 2010 May;51(5):933-44. doi: 10.1194/jlr.M000257. Epub 2009 Nov 18.
A mutation in NPC1 leads to sequestration of unesterified cholesterol in the late endosomal/lysosomal compartment of every cell culminating in the development of pulmonary, hepatic, and neurodegenerative disease. Acute administration of 2-hydroxypropyl-beta-cyclodextrin (CYCLO) rapidly overcomes this transport defect in both the 7-day-old pup and 49-day-old mature npc1(-/-) mouse, even though this compound is cleared from the body and plasma six times faster in the mature mouse than in the neonatal animal. The liberated cholesterol flows into the cytosolic ester pool, suppresses sterol synthesis, down-regulates SREBP2 and its target genes, and reduces expression of macrophage-associated inflammatory genes. These effects are seen in the liver and brain, as well as in peripheral organs like the spleen and kidney. Only the lung appears to be resistant to these effects. Forty-eight h after CYCLO administration to the 49-day-old animals, fecal acidic, but not neutral, sterol output increases, whole-animal cholesterol burden is reduced, and the hepatic and neurological inflammation is ameliorated. However, lifespan is extended only when the CYCLO is administered to the 7-day-old animals. These studies demonstrate that CYCLO administration acutely reverses the cholesterol transport defect seen in the NPC1 mouse at any age, and this reversal allows the sequestered sterol to be excreted from the body as bile acid.
NPC1 基因突变会导致未酯化胆固醇在每个细胞的晚期内体/溶酶体隔室中隔离，最终导致肺部、肝脏和神经退行性疾病的发生。急性给予 2-羟丙基-β-环糊精（CYCLO）可迅速克服 7 日龄幼鼠和 49 日龄成熟 NPC1（-/-）小鼠中的这种转运缺陷，尽管该化合物在成熟小鼠中的清除速度比在新生动物中快六倍。释放的胆固醇流入胞质酯池，抑制固醇合成，下调 SREBP2 及其靶基因，并减少巨噬细胞相关炎症基因的表达。这些影响在肝脏和大脑以及脾脏和肾脏等外周器官中都可见到。只有肺部似乎对这些影响有抵抗力。在给予 49 日龄动物 CYCLO 后 48 小时，粪便酸性而非中性固醇的排出量增加，全身胆固醇负担减轻，肝和神经炎症得到改善。然而，只有当 CYCLO 给予 7 日龄动物时，才会延长寿命。这些研究表明，在任何年龄，给予 CYCLO 均可急性逆转 NPC1 小鼠中观察到的胆固醇转运缺陷，这种逆转使隔离的固醇可作为胆汁酸从体内排出。
