O-GlcNAcylated p53 in the liver modulates hepatic glucose production

Maria J. Gonzalez-Rellan, Marcos F. Fondevila, Uxia Fernandez, Amaia Rodríguez, Marta Varela-Rey, Christelle Veyrat-Durebex, Samuel Seoane, Ganeko Bernardo, Fernando Lopitz-Otsoa, David Fernández-Ramos, Jon Bilbao, Cristina Iglesias, Eva Novoa, Cristina Ameneiro, Ana Senra, Daniel Beiroa, Juan Cuñarro, Maria Chantada-Vazquez, Maria Garcia-Vence, Susana B. Bravo, Natalia Da Silva Lima, Begoña Porteiro, Carmen Carneiro, Anxo Vidal, Sulay Tovar, Timo D. Müller, Johan Ferno, Diana Guallar, Miguel Fidalgo, Guadalupe Sabio, Stephan Herzig, Won Ho Yang, Jin Won Cho, Maria Luz Martinez-Chantar, Roman Perez-Fernandez, Miguel López, Carlos Dieguez, Jose M. Mato, Oscar Millet, Roberto Coppari, Ashwin Woodhoo, Gema Fruhbeck and Ruben Nogueiras ()
Additional contact information
Maria J. Gonzalez-Rellan: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Marcos F. Fondevila: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Uxia Fernandez: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Amaia Rodríguez: CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn)
Marta Varela-Rey: Bizkaia Technology Park
Christelle Veyrat-Durebex: University of Geneva
Samuel Seoane: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Ganeko Bernardo: Basque Research and Technology Alliance
Fernando Lopitz-Otsoa: Basque Research and Technology Alliance
David Fernández-Ramos: CIBERehd, Instituto de Salud Carlos III
Jon Bilbao: Basque Research and Technology Alliance
Cristina Iglesias: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Eva Novoa: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Cristina Ameneiro: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Ana Senra: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Daniel Beiroa: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Juan Cuñarro: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Maria Chantada-Vazquez: Santiago de Compostela
Maria Garcia-Vence: Santiago de Compostela
Susana B. Bravo: Santiago de Compostela
Natalia Da Silva Lima: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Begoña Porteiro: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Carmen Carneiro: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Anxo Vidal: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Sulay Tovar: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Timo D. Müller: German Research Center for Environmental Health (GmbH) and German Center for Diabetes Research (DZD)
Johan Ferno: Haukeland University Hospital
Diana Guallar: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Miguel Fidalgo: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Stephan Herzig: Institute for Diabetes and Cancer (IDC) and Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Center Munich
Won Ho Yang: Yonsei University
Jin Won Cho: Yonsei University
Maria Luz Martinez-Chantar: Bizkaia Technology Park
Roman Perez-Fernandez: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Miguel López: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Carlos Dieguez: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria
Jose M. Mato: University of Geneva
Oscar Millet: University of Geneva
Roberto Coppari: CIBERehd, Instituto de Salud Carlos III
Ashwin Woodhoo: IKERBASQUE, Basque Foundation for Science
Gema Fruhbeck: CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn)
Ruben Nogueiras: CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25390-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25390-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25390-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().