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O-GlcNAcylated p53 in the liver modulates hepatic glucose production.
Nat. Commun. 12:5068 (2021)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Phosphoenolpyruvate Carboxykinase; Insulin Sensitivity; Up-regulation; Metabolism; Activation; Gene; Gluconeogenesis; Transcription; Inflammation; Transferase
Language
english
Publication Year
2021
HGF-reported in Year
2021
ISSN (print) / ISBN
2041-1723
e-ISSN
2041-1723
Journal
Nature Communications
Quellenangaben
Volume: 12,
Issue: 1,
Article Number: 5068
Publisher
Nature Publishing Group
Publishing Place
London
Reviewing status
Peer reviewed
POF-Topic(s)
90000 - German Center for Diabetes Research
Research field(s)
Helmholtz Diabetes Center
PSP Element(s)
G-501900-221
G-501900-251
G-501900-251
Grants
Programa Retos
Proyectos Investigacion en Salud
Fundacion BBVA
Xunta de Galicia
Fundacion Atresmedia
Gilead Sciences International Research Scholars Program in Liver Disease
FEDER funds
ERC Consolidator Grant
European Community's H2020 Framework Program under the following grant: ERC Synergy Grant
German Research Foundation DFG
European Foundation for the Study of Diabetes
Basque Department of Industry, Tourism and Trade
National Research Foundation of Korea Grant, Ministry of Science, ICT and Future Planning
Helse Vest RHF
Western Norway Regional Health Authority
FEDER/Ministerio de Ciencia, Innovacion y Universidades-Agencia Estatal de Investigacion
Proyectos Investigacion en Salud
Fundacion BBVA
Xunta de Galicia
Fundacion Atresmedia
Gilead Sciences International Research Scholars Program in Liver Disease
FEDER funds
ERC Consolidator Grant
European Community's H2020 Framework Program under the following grant: ERC Synergy Grant
German Research Foundation DFG
European Foundation for the Study of Diabetes
Basque Department of Industry, Tourism and Trade
National Research Foundation of Korea Grant, Ministry of Science, ICT and Future Planning
Helse Vest RHF
Western Norway Regional Health Authority
FEDER/Ministerio de Ciencia, Innovacion y Universidades-Agencia Estatal de Investigacion
WOS ID
WOS:000687171500012
Scopus ID
85113240810
PubMed ID
34417460
Erfassungsdatum
2021-09-22