Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
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能量传感器 NFE2L1 的功能障碍会触发不受控制的 AMPK 信号传导和葡萄糖代谢重编程
DOI：
10.1038/s41419-022-04917-3
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发表时间：
2022-05-25
影响因子：
9
通讯作者：
Qi, Yuanming
中科院分区：
文献类型：
--
作者：
Qiu, Lu;Yang, Qiufang;Zhao, Wenshan;Xing, Yadi;Li, Peng;Zhou, Xiaowen;Ning, Haoming;Shi, Ranran;Gou, Shanshan;Chen, Yalan;Zhai, Wenjie;Wu, Yahong;Li, Guodong;Chen, Zhenzhen;Ren, Yonggang;Gao, Yanfeng;Zhang, Yiguo;Qi, Yuanming
抗氧化性转录因子NFE2L1(又称Nrf1)是氧化还原信号和代谢动态平衡的核心调节因子，其功能障碍可导致多种全身性代谢性疾病。然而，NFE2L1调节糖脂代谢的分子机制(S)仍然不清楚。在这里，我们发现NFE2L1在人肝癌细胞中的缺失导致了葡萄糖缺乏时的致死性表型，并且NFE2L1缺乏会影响葡萄糖的摄取。进一步的实验表明，NFE2L1的糖基化使其能够感知能量状态。这些结果表明，NFE2L1可以作为葡萄糖稳态的双重感受器和调节器。转录组、代谢组和海马数据进一步表明，破坏NFE2L1可以重新编程葡萄糖代谢，以加重NFE2L1沉默的肝癌细胞中的Warburg效应，并伴随线粒体损伤。共表达和免疫共沉淀实验表明，NFE2L1能直接相互作用并抑制AMPK。总的来说，NFE2L1作为一个能量感受器，通过直接与AMPK相互作用负向调节AMPK信号。新的NFE2L1/AMPK信号通路阐明了NFE2L1相关代谢性疾病的发病机制，并突出了氧化还原稳态和代谢稳态之间的串扰。
The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.
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影响因子：
30.8
作者：
通讯作者：
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
4.5
作者：
Marsh J;Mukherjee P;Seyfried TN
通讯作者：
Seyfried TN
影响因子：
5.3
作者：
Chen, LY;Kwong, M;Chan, JY
通讯作者：
Chan, JY
影响因子：
5.2
作者：
Qiu, Lu;Wang, Meng;Zhang, Yiguo
通讯作者：
Zhang, Yiguo