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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827134/ https://www.ncbi.nlm.nih.gov/pubmed/33435535 http://dx.doi.org/10.3390/biomedicines9010050 |
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author | 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 |
author_facet | 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 |
author_sort | Kim, Hyunmi |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7827134 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78271342021-01-25 GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 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 Biomedicines Article 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. MDPI 2021-01-08 /pmc/articles/PMC7827134/ /pubmed/33435535 http://dx.doi.org/10.3390/biomedicines9010050 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827134/ https://www.ncbi.nlm.nih.gov/pubmed/33435535 http://dx.doi.org/10.3390/biomedicines9010050 |
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