GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1.

Hyunmi Kim,Kwang-Hee Bae,Da Som Lee,Won Kon Kim,Tae-Jun Park,Kyoung-Jin Oh,Tae Hyeon An,Baek Soo Han,Sang Chul Lee,Eun-Woo Lee,Chul-Ho Lee

doi:10.3390/biomedicines9010050

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 (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.

Highlights

Gluconeogenesis, the de novo glucose synthesis, is important in maintaining blood glucose levels to meet the whole-body energy requirements during the state of energy exhaustion [1]
We found that whole-body GADD45β knockout (KO) mice exhibited decreased hepatic gluconeogenic gene expression and reduced blood glucose levels under fasting and high-fat diet (HFD) conditions (Figure S1A,B,D,E)
We found that GADD45β enhanced the forkhead box protein O1 (FoxO1)-induced activities of insulin response elements (IRE) and glucose-6-phosphatase catalytic subunit (G6PC) promoter (Figure S4B,C)

Summary

Introduction

Gluconeogenesis, the de novo glucose synthesis, is important in maintaining blood glucose levels to meet the whole-body energy requirements during the state of energy exhaustion [1]. Master transcription factors for regulating hepatic gluconeogenesis include cAMP response element-binding protein (CREB) and forkhead box protein O1 (FoxO1) [3]. They are mainly regulated by insulin and glucagon, the main counter regulatory hormones involved in balancing blood glucose levels [4]. By raising the cAMP levels and subsequently phosphorylates CREB, which induces the expression of gluconeogenic genes including glucose-6-phosphatase catalytic subunit (G6PC) and phosphoenolpyruvate carboxykinase-1 (PCK1) [5].

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Results

Conclusion