The histone acetyltransferases CREB-binding protein (CBP) and its paralogue p300 are transcriptional coactivators which are essential for a multitude of signaling pathways and energy homeostasis. However, the role of CBP/p300 HAT domain in regulating energy balance is still unclear. Here, C57BL/6 mice fed with either normal chow diet (NCD) or high-fat diet (HFD) were administrated with A-485, a recently reported selective inhibitor of CBP/p300 HAT activity for 1 week and the metabolic change was analyzed. The white adipose tissue (WAT) weight and adipocyte size were reduced in A-485-administrated mice, with decreased expressions of lipogenic genes and transcriptional factors. In the liver of A-485-treated mice, the lipid content and lipogenic gene expressions were lowered while the binding of forkhead box O1 (FOXO1) to glucose-6-phosphatase (G6Pc) promoter was reduced, leading to decreased expression of G6Pc. In primary mouse hepatocytes, A-485 abolished cAMP-elicited mRNA expressions of key gluconeogenic enzymes and promoted FOXO1 protein degradation via increasing its ubiquitination. Thus, A-485 inhibits lipogenesis in WAT and liver as well as decreases hepatic glucose production via preventing FOXO1 acetylation, leading to its protein degradation through a proteasome-dependent pathway. The specific inhibition of CBP/p300 HAT will provide a novel therapeutic approach for metabolic diseases.

组蛋白乙酰转移酶 CREB ​​结合蛋白 (CBP) 及其旁系同源物 p300 是转录共激活因子，对多种信号通路和能量稳态至关重要。然而，CBP/p300 HAT 结构域在调节能量平衡中的作用仍不清楚。在这里，用正常食物 (NCD) 或高脂肪饮食 (HFD) 喂养的 C57BL/6 小鼠服用 A-485，这是一种最近报道的 CBP/p300 HAT 活性选择性抑制剂 1 周，并分析了代谢变化. A-485 给药小鼠的白色脂肪组织 (WAT) 重量和脂肪细胞大小减少，脂肪生成基因和转录因子的表达减少。在 A-485 处理的小鼠的肝脏中，脂质含量和脂肪生成基因表达降低，而叉头盒O1（FOXO1）与葡萄糖-6-磷酸酶（G6Pc）启动子的结合减少，导致G6Pc的表达降低。在原代小鼠肝细胞中，A-485 消除了 cAMP 引发的关键糖异生酶的 mRNA 表达，并通过增加其泛素化促进 FOXO1 蛋白降解。因此，A-485 抑制 WAT 和肝脏中的脂肪生成，并通过阻止 FOXO1 乙酰化降低肝脏葡萄糖的产生，从而通过蛋白酶体依赖性途径导致其蛋白质降解。CBP/p300 HAT的特异性抑制将为代谢疾病提供一种新的治疗方法。A-485 消除了 cAMP 引发的关键糖异生酶的 mRNA 表达，并通过增加其泛素化促进 FOXO1 蛋白降解。因此，A-485 抑制 WAT 和肝脏中的脂肪生成，并通过阻止 FOXO1 乙酰化降低肝脏葡萄糖的产生，从而通过蛋白酶体依赖性途径导致其蛋白质降解。CBP/p300 HAT的特异性抑制将为代谢疾病提供一种新的治疗方法。A-485 消除了 cAMP 引发的关键糖异生酶的 mRNA 表达，并通过增加其泛素化促进 FOXO1 蛋白降解。因此，A-485 抑制 WAT 和肝脏中的脂肪生成，并通过阻止 FOXO1 乙酰化降低肝脏葡萄糖的产生，从而通过蛋白酶体依赖性途径导致其蛋白质降解。CBP/p300 HAT的特异性抑制将为代谢疾病提供一种新的治疗方法。