GADD45b regulates hepatic gluconeogenesis via modulating the protein stability of FoxO1

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Title
GADD45b regulates hepatic gluconeogenesis via modulating the protein stability of FoxO1
Author(s)
Hyunmi Kim; Da Som Lee; Tae Hyeon An; Tae Jun Park; Eun-Woo LeeBaek Soo HanWon Kon KimChul-Ho LeeSang Chul LeeKyoung-Jin OhKwang-Hee Bae
Bibliographic Citation
Biomedicines, vol. 9, pp. 50-50
Publication Year
2021
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.
Keyword
GADD45bGluconeogenesisFoxO1Protein stabilitycAMP signaling
ISSN
2227-9059
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/biomedicines9010050
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Research on National Challenges > Biodefense Research Center > 1. Journal Articles
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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