Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. HNF4α functions to stimulate transcription of key gluconeogenic genes. HNF4α harbors two promoters (P2 and P1) thought to be primarily active in fetal and adult livers, respectively. Here we report that the fetal version of HNF4α is required for HGP in the adult liver. This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to glucagon-stimulated upregulation of TET3, not previously shown to be involved in HGP. TET3 is recruited to the P2 promoter by FOXA2, leading to promoter demethylation and increased transcription. While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D.

中文翻译：

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肝TET3通过诱导HNF4α胎儿亚型而导致2型糖尿病。

精确控制肝葡萄糖生成（HGP）对​​于维持全身性葡萄糖稳态至关重要。HNF4α的作用是刺激关键糖异生基因的转录。HNF4α带有两个启动子（P2和P1），被认为分别在胎儿和成人肝脏中具有主要活性。在这里，我们报告HGP4在成人肝脏中需要胎儿版本的HNF4α。这种同工型在禁食后被急性诱导，并在2型糖尿病（T2D）中长期增加。响应胰高血糖素刺激的TET3上调而发生P2亚型诱导，以前未显示参与HGP。TET3被FOXA2募集到P2启动子，导致启动子去甲基化并增加转录。尽管TET3过表达增加了HGP，肝脏中TET3或P2同种型的单独敲低可改善T2D饮食和遗传小鼠模型中的葡萄糖稳态。这些研究揭示了HGP中意料之外的，保守的调节机制，并为T2D提供了潜在的治疗靶标。