Ets1-Mediated Acetylation of FoxO1 Is Critical for Gluconeogenesis Regulation during Feed-Fast Cycles
Ets1-Mediated Acetylation of FoxO1 Is Critical for Gluconeogenesis Regulation during Feed-Fast Cycles
复制标题
Ets1 介导的 FoxO1 乙酰化对于禁食周期中的糖异生调节至关重要
DOI：
10.1016/j.celrep.2019.02.035
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发表时间：
2019-03-12
期刊：
影响因子：
8.8
通讯作者：
Han, Xiao
中科院分区：
文献类型：
--
作者：
Li, Kai;Qiu, Chen;Han, Xiao
肝葡萄糖摄取和产生的稳态平衡在进料快速周期期间由激素信号精美控制。 FOXO1是调节葡萄糖稳态调节的转录因子，对响应激素信号的转化后修饰（例如乙酰化）进行了转录后修饰，但该机制仍然忽略了。通过CBP的324个辅助因子（一种众所周知的FOXO1乙酰基转移酶）的表达分析，我们将ETS1识别为FOXO1乙酰化的调节剂，它与进料速度循环高度相关。机械测定法表明，ETS1通过与CBP形成复合物，增强了FOXO1乙酰化，从而进一步促进了FOXO1核排斥并抑制其与糖原启动子的结合。功能研究进一步表明，ETS1在生理和糖尿病状态下抑制糖异生，而高胰岛素 - 远产血夹夹测定法表明肝细胞ETS1敲除小鼠具有增强的肝葡萄糖产生。我们的研究将ETS1确定为FOXO1乙酰化的增强剂，并且是响应激素信号的肝糖异生的阻遏物。
The homeostatic balance of hepatic glucose uptake and production is exquisitely controlled by hormonal signals during feed-fast cycles. FoxO1, a transcription factor that functions in the regulation of glucose homeostasis, undergoes posttranslational modifications, such as acetylation, in response to hormonal signals, yet the mechanism remains poorly elucidated. Through expression profiling of 324 co-factors of CBP, a well-known acetyl-transferase of FoxO1, we identify Ets1 as a modulator of FoxO1 acetylation that is highly associated with feed-fast cycles. Mechanistic assays suggest that Ets1 enhances FoxO1 acetylation through the formation of a complex with CBP, which further promotes FoxO1 nuclear exclusion and inhibits its binding to gluconeogenic promoters. Functional studies further reveal that Ets1 inhibits gluconeogenesis under physiological and diabetes statuses, while the hyper-insulinemic-euglycemic clamp assay suggests hepatocyte Ets1 knockout mice have enhanced hepatic glucose production. Our study identifies Ets1 as an enhancer of FoxO1 acetylation and a repressor of hepatic gluconeogenesis in response to hormonal signals.