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The Extending Spectrum of NPC1-Related Human Disorders: From Niemann–Pick C1 Disease to Obesity
Endocrine Reviews ( IF 20.3 ) Pub Date : 2018-01-09 , DOI: 10.1210/er.2017-00176
Amel Lamri 1 , Marie Pigeyre 1, 2 , William S Garver 3 , David Meyre 1, 4
Affiliation  

The Niemann–Pick type C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes/lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, as well as liver and lung failure, due to cholesterol infiltration. In humans, genome-wide association studies and post–genome-wide association studies highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Heterozygous human carriers of rare loss-of-function coding variants in NPC1 display an increased risk of morbid adult obesity. These associations have been confirmed in mice models, showing an important interaction with high-fat diet. In this review, we describe the current state of knowledge for NPC1 variants in relationship to pleiotropic effects on metabolism. We provide evidence that NPC1 gene variations may predispose to common metabolic diseases by modulating steroid hormone synthesis and/or lipid homeostasis. We also propose several important directions of research to further define the complex roles of NPC1 in metabolism. This review emphasizes the contribution of NPC1 to obesity and its metabolic complications.

中文翻译:

NPC1相关的人类疾病的扩展范围:从尼曼·匹克C1病到肥胖

Niemann-Pick C1型(NPC1)蛋白调节晚期内体/溶酶体中胆固醇和脂肪酸的转运,并在维持脂质稳态方面起着核心作用。NPC1突变在人类中引起疾病NPC1失功能,罕见的常染色体隐性脂质贮积症的特征在于渐进性和致命的神经变性,以及肝和肺衰竭,由于胆固醇浸润。在人类中,全基因组关联研究和全基因组后关联研究突显了NPC1常见变异体对成年肥胖,体脂量和2型糖尿病的影响。NPC1中罕见的功能丧失编码变体的杂合人类携带者患病的成人肥胖的风险增加。这些关联已在小鼠模型中得到证实,显示了与高脂饮食的重要相互作用。在这篇综述中,我们描述了与多效性对代谢的影响有关的NPC1变体的当前知识状态。我们提供的证据表明,NPC1基因变异可能通过调节类固醇激素合成和/或脂质体内稳态而易患常见的代谢性疾病。我们还提出了几个重要的研究方向,以进一步定义NPC1在代谢中的复杂作用。这项审查强调NPC1对肥胖及其代谢并发症的贡献。
更新日期:2018-01-09
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