Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid

被引:140
作者
Liu, Benny [1 ]
Ramirez, Charina M. [2 ]
Miller, Anna M. [3 ]
Repa, Joyce J. [1 ,3 ]
Turley, Stephen D. [1 ]
Dietschy, John M. [1 ]
机构
[1] Univ Texas SW Med Sch, Dept Internal Med, Dallas, TX 75390 USA
[2] Univ Texas SW Med Sch, Dept Pediat, Dallas, TX 75390 USA
[3] Univ Texas SW Med Sch, Dept Physiol, Dallas, TX 75390 USA
关键词
Niemann-Pick type C; neurodegeneration; liver; lung; lysosome; macrophage; SREBP2; cholesterol balance; inflammation; NIEMANN-PICK-DISEASE; CENTRAL-NERVOUS-SYSTEM; LIVER-CELL DEATH; C DISEASE; UNESTERIFIED CHOLESTEROL; MOUSE; RECEPTOR; PROTEIN; HOMEOSTASIS; TISSUES;
D O I
10.1194/jlr.M000257
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.-Liu, B., C. M. Ramirez, A. M. Miller, J. J. Repa, S. D. Turley, and J. M. Dietschy. Cyclodextrin overcomes the transport defect in nearly every organ of the newborn or mature NPC1 mouse leading to excretion of the sequestered cholesterol as bile acid. J. Lipid Res. 2010. 51: 933-944.
引用
收藏
页码:933 / 944
页数:12
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