GSK3β regulates gluconeogenic gene expression through HNF4α and FOXO1

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.