Sakamaki Jun-ichi, Daitoku Hiroaki, Kaneko Yuta, Hagiwara Ayano, Ueno Katsuya, Fukamizu Akiyoshi
Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
J Recept Signal Transduct Res. 2012 Apr;32(2):96-101. doi: 10.3109/10799893.2012.660531. Epub 2012 Mar 5.
Hepatic gluconeogenesis is important for the maintenance of blood glucose homeostasis under fasting condition. Hepatocyte nuclear factor 4α (HNF4α) 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 3β (GSK3β) regulates the expression of gluconeogenic genes through HNF4α and FOXO1. Silencing of GSK3β leads to reduction in the expression of gluconeogenic genes, including G6Pase, PEPCK, and peroxisome proliferator-activated receptor γ coactivator-1α. We show that GSK3β directly binds to both HNF4α and FOXO1. Inhibition of GSK3 by SB-216763 abolishes HNF4α-mediated activation of G6Pase promoter. We also found that overexpression of GSK3β 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.
肝糖异生对于在禁食状态下维持血糖稳态很重要。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）和磷酸烯醇丙酮酸羧激酶（PEPCK）的转录调控参与了这一过程，而这两种酶是糖异生中的限速酶。在本研究中，我们证明糖原合酶激酶3β（GSK3β）通过HNF4α和FOXO1调节糖异生基因的表达。沉默GSK3β会导致包括G6Pase、PEPCK和过氧化物酶体增殖物激活受体γ共激活因子-1α在内的糖异生基因表达降低。我们表明GSK3β直接与HNF4α和FOXO1结合。SB-216763对GSK3的抑制消除了HNF4α介导的G6Pase启动子激活。我们还发现，GSK3β的过表达以依赖其激酶活性的方式增强了FOXO1对G6Pase启动子的激活。用SB-216763处理会减弱FOXO1介导的G6Pase启动子激活。综上所述，这些结果揭示了一种以前未被认识的糖异生基因表达调控机制。
