Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.
CIBERobn, CIBER Fisiopatologia de la Obesidad y Nutricion, Spain, Spain.
Gut. 2023 Mar;72(3):472-483. doi: 10.1136/gutjnl-2021-326620. Epub 2022 May 17.
p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism.
We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D).
We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index.
These results demonstrate that p63 physiologically regulates glucose homeostasis.
p63 是 p53 蛋白家族中的一种转录因子，在发育、分化和衰老预防中具有关键作用，但它的代谢作用在很大程度上仍不清楚。本文研究了 p63 在葡萄糖代谢中的生理作用。
我们使用细胞系和小鼠模型在肝细胞中遗传操纵 p63。我们还测量了肥胖伴或不伴 2 型糖尿病（T2D）患者肝脏中的 p63。
我们发现空腹时肝脏 p63 的表达减少。肝脏特异性缺失 TAp63 的小鼠（p63LKO）在餐后和丙酮酸诱导的血糖升高。这些小鼠 SIRT1 水平升高，而在 p63LKO 小鼠中敲低 SIRT1 可使血糖正常化。在野生型小鼠中过表达 TAp63 可降低餐后、丙酮酸诱导的血糖和 SIRT1 水平。在肝细胞系中进行的研究表明，TAp63 通过抑制其转录激活来调节 SIRT1 启动子。TAp63 还介导了胰岛素对肝葡萄糖生成的抑制作用，因为沉默 TAp63 会损害胰岛素敏感性。最后，肥胖伴 T2D 患者的 TAp63 蛋白水平降低，与空腹血糖和稳态模型评估指数呈负相关。
这些结果表明，p63 生理性地调节葡萄糖稳态。
