Liu Benny, Li Hao, Repa Joyce J, Turley Stephen D, Dietschy John M
Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151, USA.
J Lipid Res. 2008 Mar;49(3):663-9. doi: 10.1194/jlr.M700525-JLR200. Epub 2007 Dec 12.
Niemann-Pick type C (NPC) disease is a multisystem disorder caused primarily by a mutation in the npc1 gene. These studies evaluated the effect of genetic background, deletion of additional genes, and administration of several agents on the age at death in a murine model of this disorder. Such factors as differing strain background or genetic drift within a given background in the npc1(-/-) mouse significantly altered the age at death and the degree of organ disease. Genetic deletion of Siat9 (GM3 synthetase) or Nr1h2 [liver X receptor (LXR)beta] shortened the life of the npc1(-/-) animals. Daily treatment of the npc1(-/-) mice with an LXR agonist or administration of a single dose of cyclodextrin, with or without the neurosteroid allopregnanolone, significantly slowed neurodegeneration and increased the lifespan of these animals. These data illustrate that the age at death of the npc1(-/-) mouse can be significantly influenced by many factors, including differences in strain background, other inactivating gene mutations (Siat9 and lxrbeta), and administration of agents such as LXR agonists and, particularly, cyclodextrin. It is currently not clear which of these effects is nonspecific or which might relate directly to the molecular defect present in the NPC1 syndrome.
尼曼-匹克C型（NPC）病是一种多系统疾病，主要由npc1基因突变引起。这些研究评估了遗传背景、其他基因缺失以及多种药物给药对该疾病小鼠模型死亡年龄的影响。诸如不同品系背景或npc1（-/-）小鼠在给定背景内的遗传漂变等因素，显著改变了死亡年龄和器官疾病程度。Siat9（GM3合成酶）或Nr1h2[肝X受体（LXR）β]的基因缺失缩短了npc1（-/-）动物的寿命。用LXR激动剂每日治疗npc1（-/-）小鼠，或给予单剂量环糊精，无论是否联合神经甾体别孕烯醇酮，均显著减缓神经退行性变并延长了这些动物的寿命。这些数据表明，npc1（-/-）小鼠的死亡年龄会受到许多因素的显著影响，包括品系背景差异、其他失活基因突变（Siat9和lxrβ）以及LXR激动剂尤其是环糊精等药物的给药。目前尚不清楚这些效应中哪些是非特异性的，哪些可能与NPC1综合征中存在的分子缺陷直接相关。
