GADD45? Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1.

ABSTRACT: 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?) 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? in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45? 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? KD mice. Further, in primary hepatocytes, GADD45? KD reduced glucose output, whereas GADD45? overexpression increased it. Mechanistically, GADD45? 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? colocalized and physically interacted with FoxO1. Additionally, GADD45? deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45? expression. Our finding demonstrates GADD45? as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.

SUBMITTER: Kim H 

PROVIDER: S-EPMC7827134 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature