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IDOL regulates systemic energy balance through control of neuronal VLDLR expression.
Nature Metabolism ( IF 18.9 ) Pub Date : 2019-10-28 , DOI: 10.1038/s42255-019-0127-7
Stephen D Lee 1 , Christina Priest 1 , Mikael Bjursell 2 , Jie Gao 1 , Douglas V Arneson 3 , In Sook Ahn 3 , Graciel Diamante 3 , J Edward van Veen 3 , Megan G Massa 3 , Anna C Calkin 1 , Jason Kim 1 , Harriet Andersén 2 , Prashant Rajbhandari 1 , Michelle Porritt 2 , Alba Carreras 2 , Andrea Ahnmark 4 , Frank Seeliger 5 , Ingela Maxvall 4 , Pernilla Eliasson 4 , Magnus Althage 4 , Peter Åkerblad 4 , Daniel Lindén 4, 6 , Tracy A Cole 7 , Richard Lee 7 , Helen Boyd 8 , Mohammad Bohlooly-Y 2 , Stephanie M Correa 3 , Xia Yang 3 , Peter Tontonoz 1 , Cynthia Hong 1
Affiliation  

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL 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 diet-induced 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, endothelium, intestine, 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 control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.

中文翻译:

IDOL 通过控制神经元 VLDLR 表达来调节全身能量平衡。

肝 X 受体通过刺激 LDL 受体诱导降解剂 (IDOL) 的转录来限制细胞脂质摄取,IDOL 是一种靶向脂蛋白受体降解的 E3 泛素连接酶。IDOL 在全身代谢中的作用尚不完全清楚。在这里,我们表明小鼠中 IDOL 的缺失通过改变食物摄入和产热来防止饮食诱导的肥胖和代谢功能障碍的发展。出乎意料的是,对组织特异性敲除小鼠的分析表明,IDOL 影响能量平衡,不是通过其在外周代谢组织(肝脏、脂肪、内皮、肠、骨骼肌)中的作用,而是通过控制神经元中的脂蛋白受体丰度。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,我们将 VLDLR 而不是 LDLR 确定为 IDOL 对能量平衡影响的主要介质。这些研究确定了神经元 IDOL-VLDLR 通路在代谢稳态和饮食诱导的肥胖中的作用。
更新日期:2019-10-28
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