GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

• Published in: Biomedicines 2021-01, Vol.9 (1), p.50
• Main Authors: Kim, Hyunmi, Lee, Da Som, An, Tae Hyeon, Park, Tae-Jun, Lee, Eun-Woo, Han, Baek Soo, Kim, Won Kon, Lee, Chul-Ho, Lee, Sang Chul, Oh, Kyoung-Jin, Bae, Kwang-Hee
• Format: Article
• Language: English
• Subjects: Acidification; Adenoviruses; AKT protein; Antibiotics; Antibodies; Blood glucose; cAMP signaling; Cyclic AMP response element-binding protein; Deoxyribonucleic acid; Diabetes mellitus (non-insulin dependent); DNA; DNA damage; Experiments; Fasting; Fatty acids; Forkhead protein; Forskolin; FoxO1; FOXO1 protein; GADD45β; Gene expression; Glucagon; Gluconeogenesis; Glucose; Glycerol; Hepatocytes; High fat diet; Insulin; Kinases; Laboratory animals; Liver; Molecular modelling; Phosphorylation; protein stability; Proteins; Transcription
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines9010050

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 (GADD45β) 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 GADD45β in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45β exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45β KD mice. Further, in primary hepatocytes, GADD45β KD reduced glucose output, whereas GADD45β overexpression increased it. Mechanistically, GADD45β 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, GADD45β colocalized and physically interacted with FoxO1. Additionally, GADD45β deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45β expression. Our finding demonstrates GADD45β as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.