Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse

被引:325
作者
Liu, Benny [1 ]
Turley, Stephen D. [1 ]
Burns, Dennis K. [2 ]
Miller, Anna M. [3 ]
Repa, Joyce J. [1 ,3 ]
Dietschy, John M. [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA
关键词
cholesterol; lysosome; cyclodextrin; liver X receptor; PICK-C DISEASE; CHOLESTEROL ACCUMULATION; ACID LIPASE; CELL DEATH; PROTEIN; GENE; CYCLODEXTRINS; HOMEOSTASIS; MICE; ENDOCYTOSIS;
D O I
10.1073/pnas.0810895106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-beta-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.
引用
收藏
页码:2377 / 2382
页数:6
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