GSK3β regulates gluconeogenic gene expression through HNF4α and FOXO1
GSK3β regulates gluconeogenic gene expression through HNF4α and FOXO1
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DOI：
10.3109/10799893.2012.660531
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发表时间：
2012-04-01
影响因子：
2.8
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Sakamaki, Jun-ichi;Daitoku, Hiroaki;Fukamizu, Akiyoshi
在禁食条件下，肝脏糖异生对维持血糖稳态具有重要意义。肝细胞核因子4α(HNF4α)和FOXO1转录因子通过对葡萄糖-6-磷酸酶(G6Pase)和磷酸烯醇式丙酮酸羧酸激酶(PEPCK)的转录调控参与了这一过程，这两种酶是糖异生中的限速酶。在这项研究中，我们证明了糖原合成酶激酶3β(GSK3β)通过HNF4α和FOXO1调节糖异生基因的表达。沉默GSK3β导致糖异生基因表达减少，包括G6Pase、PEPCK和过氧化物酶体增殖物激活受体γ辅活化子-1α。我们发现GSK3β直接与HNF4α和FOXO1结合。SB-216763抑制GSK3可取消HNF4α介导的G6Pase启动子激活。我们还发现，GSK3β的过表达增强了FOXO1对G6Pase启动子的激活，这种激活依赖于G6Pase的激酶活性。SB-216763可降低FOXO1介导的G6Pase启动子的激活。综上所述，这些结果揭示了一个以前未知的糖异生基因表达调节机制。
Hepatic gluconeogenesis is important for the maintenance of blood glucose homeostasis under fasting condition. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) and FOXO1 transcription factors have implicated in this process through transcriptional regulation of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which are rate-limiting enzymes in gluconeogenesis. In this study, we demonstrate that glycogen synthase kinase 3 beta (GSK3 beta) regulates the expression of gluconeogenic genes through HNF4 alpha and FOXO1. Silencing of GSK3 beta leads to reduction in the expression of gluconeogenic genes, including G6Pase, PEPCK, and peroxisome proliferator-activated receptor gamma coactivator-1 alpha. We show that GSK3 beta directly binds to both HNF4 alpha and FOXO1. Inhibition of GSK3 by SB-216763 abolishes HNF4 alpha-mediated activation of G6Pase promoter. We also found that overexpression of GSK3 beta potentiates G6Pase promoter activation by FOXO1 in a manner dependent on its kinase activity. Treatment of SB-216763 diminishes FOXO1-mediated activation of G6Pase promoter. Taken together, these results reveal a previously unrecognized mechanism for the regulation of gluconeogenic gene expression.