HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes.

IF 6.4 1区生物学 Q1 BIOLOGY

eLife Pub Date : 2025-06-03 DOI:10.7554/eLife.103663

Hongchen Li, Xinchao Zhang, Xiaoben Liang, Shuyan Li, Ziyi Cui, Xinyu Zhao, Kai Wang, Bingbing Zha, Haijie Ma, Ming Xu, Lei Lv, Yanping Xu

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Abstract

The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.

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HNF4α-TET2-FBP1轴参与糖异生和2型糖尿病。

糖异生的控制是葡萄糖稳态和2型糖尿病（T2D）病理的关键。在这里，我们发现了TET2在糖异生调控中的新功能。在小鼠中，禁食和高脂肪饮食（HFD）都刺激TET2的表达，而TET2敲除会损害葡萄糖的产生。在机制上，FBP1是糖异生的限速酶，在肝细胞中受到TET2的正向调节。TET2被HNF4α募集，参与FBP1启动子的去甲基化，并激活其在胰高血糖素刺激下的表达。此外，二甲双胍治疗增加了HNF4α在Ser313上的磷酸化，从而阻止了其与TET2的相互作用，从而降低了FBP1的表达水平，改善了T2D的病理。综上所述，我们发现了一个控制糖异生的HNF4α-TET2-FBP1轴，这有助于二甲双胍对T2D的治疗效果，为临床治疗T2D提供了一个潜在的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

eLife BIOLOGY-

CiteScore

12.90

自引率

3.90%

发文量

3122

审稿时长

17 weeks

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