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 (GADD45β) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesi...
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MDPI AG
2021-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/1/50 |
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| author | Hyunmi Kim Da Som Lee Tae Hyeon An Tae-Jun Park Eun-Woo Lee Baek Soo Han Won Kon Kim Chul-Ho Lee Sang Chul Lee Kyoung-Jin Oh Kwang-Hee Bae |
| author_facet | Hyunmi Kim Da Som Lee Tae Hyeon An Tae-Jun Park Eun-Woo Lee Baek Soo Han Won Kon Kim Chul-Ho Lee Sang Chul Lee Kyoung-Jin Oh Kwang-Hee Bae |
| author_sort | Hyunmi Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:30:53Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-09T05:30:53Z |
| publishDate | 2021-01-01 |
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| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-020405cc2e314c0c911478a0098143632023-12-03T12:32:19ZengMDPI AGBiomedicines2227-90592021-01-01915010.3390/biomedicines9010050GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1Hyunmi Kim0Da Som Lee1Tae Hyeon An2Tae-Jun Park3Eun-Woo Lee4Baek Soo Han5Won Kon Kim6Chul-Ho Lee7Sang Chul Lee8Kyoung-Jin Oh9Kwang-Hee Bae10Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaIncreased 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.https://www.mdpi.com/2227-9059/9/1/50GADD45βgluconeogenesisFoxO1protein stabilitycAMP signaling |
| spellingShingle | Hyunmi Kim Da Som Lee Tae Hyeon An Tae-Jun Park Eun-Woo Lee Baek Soo Han Won Kon Kim Chul-Ho Lee Sang Chul Lee Kyoung-Jin Oh Kwang-Hee Bae GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 Biomedicines GADD45β gluconeogenesis FoxO1 protein stability cAMP signaling |
| title | GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
| title_full | GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
| title_fullStr | GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
| title_full_unstemmed | GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
| title_short | GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
| title_sort | gadd45β regulates hepatic gluconeogenesis via modulating the protein stability of foxo1 |
| topic | GADD45β gluconeogenesis FoxO1 protein stability cAMP signaling |
| url | https://www.mdpi.com/2227-9059/9/1/50 |
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