Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease
Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease
复制标题
DOI：
10.1002/hep.20868
复制
发表时间：
2005-10-01
期刊：
影响因子：
13.5
通讯作者：
Dietschy, JM
中科院分区：
文献类型：
--
作者：
Beltroy, EP;Richardson, JA;Dietschy, JM
Niemann-Pick C 型 (NPC) 疾病是由 NPC1 基因突变引起的，该基因编码一种蛋白质，该蛋白质参与未酯化胆固醇从晚期内体/溶酶体区室到体内几乎每个细胞的细胞质中代谢活跃的甾醇库的净移动。尽管早期出版物强调携带这种突变的儿童会发生神经退行性疾病，但最近的临床信息表明，严重的肝脏疾病也是这种综合征的一个重要组成部分。因此，这些研究的目的是表征具有相同突变的小鼠中观察到的肝功能障碍。 NPC 小鼠出现明显的肝肿大，在 5 至 6 周龄时达到体重的 8%。肝脏大小的增加与胆固醇含量的线性增加以及肝细胞和巨噬细胞中无定形细胞内含物的积累有关。在出生后几周内，血浆碱性磷酸酶水平显着升高，就像患有这种疾病的婴儿一样。 4至5周龄时，血浆转氨酶水平也突然升高。组织学上，此时存在细胞凋亡，但没有胶原或糖原过量沉积。 Caspase 1、Caspase 6 以及与甾醇生物合成和胆汁酸形成相关的几种酶的 mRNA 表达升高。总之，鼻咽癌小鼠患有与鼻咽癌婴儿相似的肝病，并且代表了探索这种肝病中发生的分子事件的相关模型。
Niemann-Pick type C (NPC) disease develops as a result of mutations in the NPC1 gene that encodes a protein involved in the net movement of unesterified cholesterol from the late endosomal/lysosomal compartment to the metabolically active pool of sterol in the cytosol of virtually every cell in the body. Although early publications emphasized the neurodegeneration occurring in children with this mutation, more recent clinical information suggests that serious liver disease also is an important part of this syndrome. These studies, therefore, were undertaken to characterize the liver dysfunction seen in mice with this same mutation. The NPC mouse develops significant hepatomegaly that reaches 8% of body weight at 5 to 6 weeks of age. This increase in liver size is associated with a linear increase in cholesterol content and with accumulation of amorphous cellular inclusions in both hepatocytes and macrophages. During the few weeks after birth, significant elevation of the plasma alkaline phosphatase level occurs, as also is seen in the human infant with this disease. At 4 to 5 weeks of age, plasma aminotransferase levels also rise abruptly. Histologically, at this time there is apoptosis, but no excess deposition of collagen or glycogen. mRNA expression is elevated for caspase 1, caspase 6, and several enzymes associated with sterol biosynthesis and bile acid formation. In conclusion, the NPC mouse has liver disease similar to that seen in the NPC infant and represents a relevant model for exploring the molecular events occurring in this form of liver disease.