GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

Increased hepatic gluconeogenesis is one of the main contributors to the development of type 2 diabetes. Recently, it has been reported that growth arrest and DNA damage-inducible 45 beta (GADD45 beta) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesis. Here, this study aimed to establish the molecular mechanisms underlying the novel role of GADD45 beta in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45 beta exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45 beta KD mice. Further, in primary hepatocytes, GADD45 beta KD reduced glucose output, whereas GADD45 beta overexpression increased it. Mechanistically, GADD45 beta did not affect Akt-mediated forkhead box protein O1 (FoxO1) phosphorylation and forskolin-induced cAMP response element-binding protein (CREB) phosphorylation. Rather it increased FoxO1 transcriptional activity via enhanced protein stability of FoxO1. Further, GADD45 beta colocalized and physically interacted with FoxO1. Additionally, GADD45 beta deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45 beta expression. Our finding demonstrates GADD45 beta as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.

Automated summary

GADD45 beta plays a crucial role in hepatic gluconeogenesis, with its overexpression increasing glucose output and deficiency leading to downregulation of gluconeogenic gene expression. GADD45 beta regulates FoxO1 transcriptional activity by enhancing its protein stability, thus controlling hepatic gluconeogenesis.