O-GlcNAcylated p53 in the liver modulates hepatic glucose production.
Acetylglucosamine
/ metabolism
Animals
Base Sequence
Caloric Restriction
Cell Line
Colforsin
/ pharmacology
Diabetes Mellitus, Type 2
/ complications
Epinephrine
/ metabolism
Glucagon
/ metabolism
Glucocorticoids
/ metabolism
Gluconeogenesis
/ drug effects
Glucose
/ metabolism
Glycosylation
Hepatocytes
/ drug effects
Humans
Hydrocortisone
/ metabolism
Hyperglycemia
/ complications
Insulin Resistance
Intracellular Signaling Peptides and Proteins
/ metabolism
Liver
/ drug effects
Mice, Inbred C57BL
Mice, Knockout
Obesity
/ complications
Phosphoenolpyruvate Carboxykinase (GTP)
/ metabolism
Promoter Regions, Genetic
/ genetics
Protein Binding
/ drug effects
Protein Stability
/ drug effects
Pyruvic Acid
/ metabolism
RNA, Messenger
/ genetics
Transcription, Genetic
/ drug effects
Tumor Suppressor Protein p53
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 08 2021
20 08 2021
Historique:
received:
26
06
2020
accepted:
06
08
2021
entrez:
21
8
2021
pubmed:
22
8
2021
medline:
1
9
2021
Statut:
epublish
Résumé
p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.
Identifiants
pubmed: 34417460
doi: 10.1038/s41467-021-25390-0
pii: 10.1038/s41467-021-25390-0
pmc: PMC8379189
doi:
Substances chimiques
Glucocorticoids
0
Intracellular Signaling Peptides and Proteins
0
RNA, Messenger
0
Tumor Suppressor Protein p53
0
Colforsin
1F7A44V6OU
Pyruvic Acid
8558G7RUTR
Glucagon
9007-92-5
Pck1 protein, mouse
EC 4.1.1.32
Phosphoenolpyruvate Carboxykinase (GTP)
EC 4.1.1.32
Glucose
IY9XDZ35W2
Acetylglucosamine
V956696549
Hydrocortisone
WI4X0X7BPJ
Epinephrine
YKH834O4BH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5068Informations de copyright
© 2021. The Author(s).
Références
Diabetologia. 1988 Nov;31(11):798-805
pubmed: 3234634
Pharmacol Res. 2018 May;131:75-86
pubmed: 29580896
J Biol Chem. 2003 Jul 11;278(28):25395-400
pubmed: 12734185
Biochem Soc Trans. 2014 Aug;42(4):798-803
pubmed: 25109960
Annu Rev Biochem. 1997;66:581-611
pubmed: 9242918
Cell Metab. 2013 Nov 5;18(5):617-33
pubmed: 23954639
JCI Insight. 2019 Feb 26;5:
pubmed: 30830873
Proc Natl Acad Sci U S A. 1982 Sep;79(17):5137-41
pubmed: 6291025
Trends Endocrinol Metab. 2013 Jun;24(6):301-9
pubmed: 23647930
Endocrinology. 1997 Jun;138(6):2601-9
pubmed: 9165054
Cell Metab. 2009 May;9(5):417-27
pubmed: 19416712
Nat Rev Mol Cell Biol. 2015 Jul;16(7):393-405
pubmed: 26122615
Nat Cell Biol. 2006 Oct;8(10):1074-83
pubmed: 16964247
Am J Physiol. 1999 Aug;277(2):E352-60
pubmed: 10444432
EMBO Mol Med. 2010 Sep;2(9):338-48
pubmed: 20721988
Eur J Biochem. 1991 May 8;197(3):815-8
pubmed: 2029909
Hepatology. 2005 Jun;41(6):1313-21
pubmed: 15915461
J Clin Invest. 1987 Mar;79(3):777-81
pubmed: 3546378
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7413-8
pubmed: 20368426
BMC Cancer. 2014 Jul 29;14:548
pubmed: 25070371
J Biol Chem. 2008 Mar 7;283(10):6050-7
pubmed: 18174169
J Biol Chem. 2008 Jun 13;283(24):16283-92
pubmed: 18420577
Cancer Metab. 2013 Feb 04;1(1):9
pubmed: 24280180
Nat Commun. 2013;4:2508
pubmed: 24149070
Arch Biochem Biophys. 2009 Nov;491(1-2):46-52
pubmed: 19799852
Diabetes. 2008 Aug;57(8):2199-210
pubmed: 18443203
Mol Cell Biol. 2010 Dec;30(24):5787-94
pubmed: 20956556
Int J Mol Sci. 2018 Mar 08;19(3):
pubmed: 29518025
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7467-72
pubmed: 20231469
Science. 2008 Mar 7;319(5868):1402-5
pubmed: 18323454
Mol Endocrinol. 2007 Jul;21(7):1513-25
pubmed: 17456792
Cell Metab. 2007 Jun;5(6):438-49
pubmed: 17550779
Cell Cycle. 2013 Mar 1;12(5):753-61
pubmed: 23343762
Cell Metab. 2012 Aug 8;16(2):226-37
pubmed: 22883232
J Biol Chem. 2002 Jun 28;277(26):23301-7
pubmed: 11964395
Diabetes Care. 2015 Jan;38 Suppl:S8-S16
pubmed: 25537714
Int J Obes (Lond). 2014 May;38(5):737-45
pubmed: 23999197
Cell Cycle. 2007 May 2;6(9):1006-10
pubmed: 17457049
Nat Cell Biol. 2008 May;10(5):611-8
pubmed: 18391940
Lab Anim. 2000 Jul;34(3):301-6
pubmed: 11037125
Hepatology. 2021 Jul;74(1):148-163
pubmed: 33284502
Nat Cell Biol. 2011 Mar;13(3):310-6
pubmed: 21336310
FASEB J. 2017 Feb;31(2):732-742
pubmed: 27811061
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9151-4
pubmed: 8090784
Mol Metab. 2018 Nov;17:122-133
pubmed: 30224299
J Clin Endocrinol Metab. 2012 Dec;97(12):4640-9
pubmed: 23066116
J Biol Chem. 2009 Feb 6;284(6):3425-32
pubmed: 19073609
Hepatology. 2009 Dec;50(6):1963-71
pubmed: 19821526
Nat Commun. 2017 May 08;8:15111
pubmed: 28480888
Nat Rev Mol Cell Biol. 2017 Jul;18(7):452-465
pubmed: 28488703
Mol Metab. 2018 Feb;8:132-143
pubmed: 29290620
N Engl J Med. 2013 Mar 14;368(11):1027-32
pubmed: 23484829
Trends Biochem Sci. 2010 Oct;35(10):547-55
pubmed: 20466550
Nat Med. 2009 Sep;15(9):1082-7
pubmed: 19718037
Trends Endocrinol Metab. 2013 Apr;24(4):184-9
pubmed: 23245767
J Biol Chem. 2008 May 9;283(19):13009-20
pubmed: 18353774
Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16259-64
pubmed: 21930938
Nature. 2008 Feb 21;451(7181):964-9
pubmed: 18288188
ACS Chem Biol. 2015 Jun 19;10(6):1392-7
pubmed: 25751766
Adv Cyclic Nucleotide Res. 1975;5:519-32
pubmed: 165683
Horm Mol Biol Clin Investig. 2014 Aug;19(2):117-28
pubmed: 25390020
Diabetologia. 1994 Aug;37(8):797-807
pubmed: 7988782
Nat Commun. 2016 Jun 06;7:11740
pubmed: 27265727
Cell Metab. 2012 May 2;15(5):739-51
pubmed: 22503562
Trends Endocrinol Metab. 2012 Nov;23(11):567-75
pubmed: 22819212
Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1226-31
pubmed: 25583513
PLoS One. 2011 Apr 19;6(4):e18959
pubmed: 21526146
Cell Rep. 2015 Jul 21;12(3):361-70
pubmed: 26166568
Cell. 2006 Jul 14;126(1):107-20
pubmed: 16839880
PLoS One. 2013 Nov 28;8(11):e81866
pubmed: 24312371
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10684-9
pubmed: 25009184