NieMann- Pick 病（Niemann –Pick’sudisease） 是一种按单纯孟德尔隐性遗传规律遗传的疾病。它让胆固醇在细胞中积累，导致大脑损伤和死亡。主要有关酶缺乏引起神经髓鞘磷脂、胆固醇及其他磷脂在肝、脾的内皮细胞及脑部沉积引起。临床表现有肝、脾肿大，神经系统症状，聋、盲及智力低下。视网膜黄斑部有磷脂沉积者亦可见樱红斑。本病为进行性，多在发病数年后死亡。
PNAS Published online before print January 26, 2009, doi: 10.1073/pnas.0810895106
Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse
Benny Liua, Stephen D. Turleya, Dennis K. Burnsb, Anna M. Millerc, Joyce J. Repaac and John M. Dietschya1
aDepartments of aInternal Medicine,
cPhysiology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1−/− mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-β-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg·d−1·kg−1, treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg·d−1·kg−1. By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.