Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
Key Laboratory of the Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing 211166, China.
Cell Rep. 2019 Mar 12;26(11):2998-3010.e5. doi: 10.1016/j.celrep.2019.02.035.
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 hyperinsulinemic-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.
在进食-禁食循环期间，激素信号对肝脏葡萄糖摄取和产生的体内平衡进行了精细的控制。FoxO1 是一种在葡萄糖稳态调节中起作用的转录因子，它会发生翻译后修饰，如乙酰化，以响应激素信号，但机制仍未得到充分阐明。通过对 CBP 的 324 个共因子的表达谱进行分析，CBP 是 FoxO1 的一种已知乙酰转移酶，我们确定 Ets1 是 FoxO1 乙酰化的调节剂，它与进食-禁食循环高度相关。机制分析表明，Ets1 通过与 CBP 形成复合物来增强 FoxO1 的乙酰化，这进一步促进了 FoxO1 的核输出，并抑制了其与糖异生启动子的结合。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-正常血糖钳夹试验表明肝细胞 Ets1 敲除小鼠的肝脏葡萄糖产生增强。我们的研究确定了 Ets1 作为 FoxO1 乙酰化的增强子和激素信号响应的肝脏糖异生的抑制剂。
