IDOL regulates systemic energy balance through control of neuronal VLDLR expression
IDOL regulates systemic energy balance through control of neuronal VLDLR expression
复制标题
DOI：
10.1038/s42255-019-0127-7
复制
发表时间：
2019-11-01
影响因子：
20.8
通讯作者：
Hong, Cynthia
中科院分区：
文献类型：
--
作者：
Lee, Stephen D.;Priest, Christina;Hong, Cynthia
肝X受体通过刺激低密度脂蛋白受体（IDOL）的诱导降解酶的转录来限制细胞脂质摄取，这是一种针对脂蛋白受体降解的E3泛素连接酶。IDOL在全身代谢中的作用尚不完全清楚。本研究表明，通过改变食物摄入和产热作用，小鼠体内IDOL的缺失可以防止饮食性肥胖和代谢功能障碍的发生。出乎意料的是，对组织特异性敲除小鼠的分析显示，IDOL影响能量平衡，不是通过其在外周代谢组织（肝脏、脂肪组织、内皮、肠和骨骼肌）中的作用，而是通过控制神经元中脂蛋白受体的丰度。下丘脑的单细胞RNA测序表明，IDOL缺失改变了与代谢控制相关的基因表达。最后，我们确定了极低密度脂蛋白受体（VLDLR）而不是低密度脂蛋白受体（LDLR）作为IDOL影响能量平衡的主要中介。这些数据确定了神经元IDOL-VLDLR通路在代谢平衡和饮食诱导的肥胖中的作用。
Liver X receptors limit cellular lipid uptake by stimulating the transcription of inducible degrader of the low-density lipoprotein receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of dietinduced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose tissue, endothelium, intestine, and skeletal muscle) but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to the control of metabolism. Finally, we identified very low-density lipoprotein receptor (VLDLR) rather than low-density lipoprotein receptor (LDLR) as the primary mediator of the effects of IDOL on energy balance. These data identify a role for the neuronal IDOL-VLDLR pathway in metabolic homoeostasis and diet-induced obesity.