Downregulation of Keap1 Confers Features of a Fasted Metabolic State.
Downregulation of Keap1 Confers Features of a Fasted Metabolic State.
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DOI：
10.1016/j.isci.2020.101638
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发表时间：
2020-10-23
期刊：
影响因子：
5.8
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
--
作者：
Knatko EV;Tatham MH;Zhang Y;Castro C;Higgins M;Dayalan Naidu S;Leonardi C;de la Vega L;Honda T;Griffin JL;Hay RT;Dinkova-Kostova AT
转录因子核因子2红系P45相关因子2(Nrf2)及其主要负调控因子Kelch样ECH相关蛋白1(Keap1)处于氧化还原和中间代谢的交界处，允许在氧化、炎症和代谢应激条件下适应和生存。NRF2是氧化还原动态平衡的主要决定因素，对线粒体的功能和完整性以及细胞生物能量学都有贡献。利用蛋白质组学和脂质组学，我们发现，在小鼠中，Keap1的基因下调，以及随之而来的Nrf2激活到药理相关的水平，导致羧酸酯酶1(CES1)和酰基辅酶A氧化酶2(Acox2)的上调，降低甘油三酯水平，并改变脂体。伴随而来的是肝脏三磷酸腺苷-柠檬酸裂解酶(Acly)的下调和乙酰辅酶A水平的降低，这是自噬的触发因素。这些发现表明，Keap1的下调具有快速代谢状态的特征，这是Keap1靶向药物Nrf2激活剂药物开发的一个重要考虑因素。Keap1在小鼠体内的下调增加CES1和Acox2并降低甘油三酯水平Keap1/Nrf2的遗传干扰改变小鼠脂体Keap1的表达减少肝脏乙酰辅酶A水平缺失结构性活性Nrf2减少微管蛋白乙酰化和自噬通量人类代谢；分子生物学；OMICS
Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory, and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglyceride levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators. Keap1 downregulation in mice increases Ces1 and Acox2 and decreases triglyceride levels Genetic interference with Keap1/Nrf2 alters the murine lipidome Reduced expression of Keap1 lowers hepatic levels of acetyl-CoA Deleting constitutively active Nrf2 decreases tubulin acetylation and autophagic flux Human Metabolism; Molecular Biology; Omics
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影响因子：
17.1
作者：
Axelsson, Annika S.;Tubbs, Emily;Rosengren, Anders H.
通讯作者：
Rosengren, Anders H.
影响因子：
19
作者：
Csordás G;Weaver D;Hajnóczky G
通讯作者：
Hajnóczky G
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca