PMID- 33435535
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210218
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 9
IP  - 1
DP  - 2021 Jan 8
TI  - GADD45beta Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of 
      FoxO1.
LID - 10.3390/biomedicines9010050 [doi]
LID - 50
AB  - 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 (GADD45beta) 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 
      GADD45beta in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and 
      adenovirus-mediated knockdown (KD) mice of GADD45beta exhibited decreased hepatic 
      gluconeogenic gene expression concomitant with reduced blood glucose levels under 
      fasting and HFD conditions, but showed a more pronounced effect in GADD45beta KD 
      mice. Further, in primary hepatocytes, GADD45beta KD reduced glucose output, whereas 
      GADD45beta overexpression increased it. Mechanistically, GADD45beta 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, GADD45beta colocalized and physically interacted with FoxO1. 
      Additionally, GADD45beta deficiency potentiated insulin-mediated suppression of 
      hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45beta 
      expression. Our finding demonstrates GADD45beta as a novel and essential regulator 
      of hepatic gluconeogenesis. It will provide a deeper understanding of the 
      FoxO1-mediated gluconeogenesis.
FAU - Kim, Hyunmi
AU  - Kim H
AUID- ORCID: 0000-0002-5596-4320
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Lee, Da Som
AU  - Lee DS
AUID- ORCID: 0000-0002-6535-7583
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - An, Tae Hyeon
AU  - An TH
AUID- ORCID: 0000-0001-8339-767X
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Park, Tae-Jun
AU  - Park TJ
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
FAU - Lee, Eun-Woo
AU  - Lee EW
AUID- ORCID: 0000-0002-5156-0003
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
FAU - Han, Baek Soo
AU  - Han BS
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Kim, Won Kon
AU  - Kim WK
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Lee, Chul-Ho
AU  - Lee CH
AUID- ORCID: 0000-0002-6996-5746
AD  - Laboratory Animal Resource Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
FAU - Lee, Sang Chul
AU  - Lee SC
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Oh, Kyoung-Jin
AU  - Oh KJ
AUID- ORCID: 0000-0002-2224-7202
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
FAU - Bae, Kwang-Hee
AU  - Bae KH
AUID- ORCID: 0000-0002-5868-2556
AD  - Metabolic Regulation Research Center, Korea Research Institute of Bioscience and 
      Biotechnology (KRIBB), Daejeon 34141, Korea.
AD  - Department of Functional Genomics, KRIBB School of Bioscience, Korea University 
      of Science and Technology (UST), Daejeon 34141, Korea.
LA  - eng
GR  - KGM1052011/Korea Research Institute of Bioscience and Biotechnology/
GR  - 2016R1C1B2010257/National Research Foundation of Korea/
GR  - 2017M3A9C4065954/National Research Foundation of Korea/
GR  - 2020R1A2C2102308/National Research Foundation of Korea/
GR  - 2020R1A2C2007111/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20210108
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC7827134
OTO - NOTNLM
OT  - FoxO1
OT  - GADD45beta
OT  - cAMP signaling
OT  - gluconeogenesis
OT  - protein stability
COIS- The authors declare no conflict of interest.
EDAT- 2021/01/14 06:00
MHDA- 2021/01/14 06:01
PMCR- 2021/01/08
CRDT- 2021/01/13 01:02
PHST- 2020/12/08 00:00 [received]
PHST- 2020/12/26 00:00 [revised]
PHST- 2021/01/07 00:00 [accepted]
PHST- 2021/01/13 01:02 [entrez]
PHST- 2021/01/14 06:00 [pubmed]
PHST- 2021/01/14 06:01 [medline]
PHST- 2021/01/08 00:00 [pmc-release]
AID - biomedicines9010050 [pii]
AID - biomedicines-09-00050 [pii]
AID - 10.3390/biomedicines9010050 [doi]
PST - epublish
SO  - Biomedicines. 2021 Jan 8;9(1):50. doi: 10.3390/biomedicines9010050.