Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
PLoS One. 2014 Apr 21;9(4):e95598. doi: 10.1371/journal.pone.0095598. eCollection 2014.
The Niemann-Pick disease, type C1 (NPC1) gene encodes a transmembrane protein involved in cholesterol efflux from the lysosome. SNPs within NPC1 have been associated with obesity and type 2 diabetes, and mice heterozygous or null for NPC1 are insulin resistant. However, the molecular mechanism underpinning this association is currently undefined. This study aimed to investigate the effects of inhibiting NPC1 function on insulin action in adipocytes. Both pharmacological and genetic inhibition of NPC1 impaired insulin action. This impairment was evident at the level of insulin signalling and insulin-mediated glucose transport in the short term and decreased GLUT4 expression due to reduced liver X receptor (LXR) transcriptional activity in the long-term. These data show that cholesterol homeostasis through NPC1 plays a crucial role in maintaining insulin action at multiple levels in adipocytes.
尼曼-匹克病 C1 型（NPC1）基因编码一种参与溶酶体胆固醇外排的跨膜蛋白。NPC1 内的单核苷酸多态性与肥胖和 2 型糖尿病有关，NPC1 杂合子或缺失的小鼠对胰岛素有抗性。然而，这种关联的分子机制目前尚不清楚。本研究旨在探讨抑制 NPC1 功能对脂肪细胞中胰岛素作用的影响。NPC1 的药理学和遗传抑制均损害了胰岛素的作用。这种损伤在短期的胰岛素信号和胰岛素介导的葡萄糖转运水平以及长期的由于肝 X 受体（LXR）转录活性降低导致 GLUT4 表达减少方面均有体现。这些数据表明，通过 NPC1 的胆固醇稳态在多个水平上在脂肪细胞中维持胰岛素作用方面发挥着关键作用。
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