Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
UMR Dynamique Musculaire et Métabolisme, INRA-CAMPUS SUPAGRO 2 place Viala, Montpellier Cedex 2, France.
Mol Metab. 2018 May;11:104-112. doi: 10.1016/j.molmet.2018.02.011. Epub 2018 Feb 26.
Aberrant hepatic glucose production contributes to the development of hyperglycemia and is a hallmark of type 2 diabetes. In a recent study, we showed that the transcription factor E2F1, a component of the cell cycle machinery, contributes to hepatic steatosis through the transcriptional regulation of key lipogenic enzymes. Here, we investigate if E2F1 contributes to hyperglycemia by regulating hepatic gluconeogenesis.
We use different genetic models to investigate if E2F1 regulates gluconeogenesis in primary hepatocytes and in vivo. We study the impact of depleting E2F1 or inhibiting E2F1 activity in diabetic mouse models to evaluate if this transcription factor contributes to hyperglycemia during insulin resistance. We analyze E2F1 mRNA levels in the livers of human diabetic patients to assess the relevance of E2F1 in human pathophysiology.
Lack of E2F1 impaired gluconeogenesis in primary hepatocytes. Conversely, E2F1 overexpression increased glucose production in hepatocytes and in mice. Several genetic models showed that the canonical CDK4-RB1-E2F1 pathway is directly involved in this regulation. E2F1 mRNA levels were increased in the livers from human diabetic patients and correlated with the expression of the gluconeogenic enzyme Pck1. Genetic invalidation or pharmacological inhibition of E2F1 improved glucose homeostasis in diabetic mouse models.
Our study unveils that the transcription factor E2F1 contributes to mammalian glucose homeostasis by directly controlling hepatic gluconeogenesis. Together with our previous finding that E2F1 promotes hepatic steatosis, the data presented here show that E2F1 contributes to both hyperlipidemia and hyperglycemia in diabetes, suggesting that specifically targeting E2F1 in the liver could be an interesting strategy for therapies against type 2 diabetes.
异常的肝葡萄糖生成导致高血糖的发生，是 2 型糖尿病的一个标志。在最近的一项研究中，我们表明细胞周期机制的转录因子 E2F1 通过关键的脂肪生成酶的转录调控，导致肝脂肪变性。在这里，我们研究 E2F1 是否通过调节肝糖异生来导致高血糖。
我们使用不同的遗传模型来研究 E2F1 是否在原代肝细胞和体内调节糖异生。我们研究了在糖尿病小鼠模型中耗尽 E2F1 或抑制 E2F1 活性的影响，以评估该转录因子是否在胰岛素抵抗期间导致高血糖。我们分析了人类糖尿病患者肝脏中的 E2F1 mRNA 水平，以评估 E2F1 在人类病理生理学中的相关性。
缺乏 E2F1 可损害原代肝细胞中的糖异生。相反，E2F1 的过表达增加了肝细胞和小鼠中的葡萄糖产生。几种遗传模型表明，经典的 CDK4-RB1-E2F1 途径直接参与了这种调节。人类糖尿病患者肝脏中的 E2F1 mRNA 水平升高，与糖异生酶 Pck1 的表达相关。E2F1 的遗传失活或药理学抑制改善了糖尿病小鼠模型的葡萄糖稳态。
我们的研究揭示了转录因子 E2F1 通过直接控制肝糖异生，有助于哺乳动物的葡萄糖稳态。与我们之前发现的 E2F1 促进肝脂肪变性的发现一起，这里呈现的数据表明 E2F1 有助于糖尿病中的高脂血症和高血糖，这表明在肝脏中特异性靶向 E2F1 可能是针对 2 型糖尿病的治疗的一个有趣策略。
