GSK3β regulates gluconeogenic gene expression through HNF4α and FOXO1

Abstract

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.

Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin

“…Insulin indirectly activates PI3K, which in turn increases the activity of Akt for FoxO1 phosphorylation and leads to the exclusion of FoxO1 from the nucleus to cytosol. Gsk3, which is inactivated by Akt, has been reported to potentiate FoxO1 activity for Pepck and G6Pase expression ( 42,43 ). Our data showed that inhibiting Gsk3 activity mimicked insulin repression on GC-induced Angptl4 expression.…”

Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids

“…Mechanistically, in the presence of excess amino acids, we found that upregulation of Notch1 protein levels resulted in the high expression of Rbp-Jk and Hes1 proteins, thereby enhancing FoxO1 protein levels. FoxO1 is a mediator of insulin signaling and plays an important role in maintaining glucose homeostasis (36) through transcriptional regulation of G6Pase and PEPCK, which are rate-limiting enzymes in the regulation of hepatic gluconeogenesis (43). Thus, activation of Notch1 may mediate insulin resistance in a FoxO1-dependent manner.…”

β-N-methylamino-L-alanine induces changes in both GSK3 and TDP-43 in human neuroblastoma

“…After stimulation, GSK3β is released from protein anchors and is translocated to nucleus, where produces cell death (Bijur and Jope, 2001). Moreover, it has been implicated in important cellular functions achieved by GSK3 phosphorylation of numerous transcription factors (Sakamaki et al, 2012). The results described herein indicate that the toxicity of L-BMAA would imply an increase of the synthesis of GSK3β and a slight decrease of the inactive form of the enzyme.…”