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.
| Original language | English |
|---|---|
| Article number | 5068 |
| Journal | Nature communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2021 Dec 1 |
Bibliographical note
Funding Information:This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (C.D.: BFU2017-87721; M.L.: RTI2018–101840-B-I00; R.N.: RTI2018-099413-B-I00; M.L.M.-C: SAF2017-87301-R; A.W.: RTI2018-097503-B-I00, and SAF2015-62588-ERC), Xunta de Galicia (M.L.: 2016-PG068; R.N.: 2015-CP080 and 2016-PG057), Fundación BBVA (R.N., A.W., G.S., and M.L.M.-C.), Programa Retos (M.L.M.-C: RTC2019-007125-1), Proyectos Investigación en Salud (M.L.M.-C: DTS20/00138), Fundación Atresmedia (M.L. and R.N.), Gilead Sciences International Research Scholars Program in Liver Disease (M.V.-R.), the Western Norway Regional Health Authority; Helse Vest RHF (J.F.), National Research Foundation of Korea Grant, Ministry of Science, ICT and Future Planning (J.W.C. and W.H.Y.: NRF-2016R1A5A1010764), Basque Department of Industry, Tourism and Trade (A.W.) and European Foundation for the Study of Diabetes (R.N. and G.S.), the German research foundation DFG (TRR152 and TRR296)/T.D.M.). The research leading to these results has also received funding from the European Community’s H2020 Framework Program under the following grant: ERC Synergy Grant-2019-WATCH-810331 to R.N. and ERC Consolidator Grant (865157-MYERIBO) to A.W. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd). CIBERobn and CIBERehd are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644).
Publisher Copyright:
© 2021, The Author(s).
All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- General
- Physics and Astronomy(all)
