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O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

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.

SUBMITTER: Gonzalez-Rellan MJ

PROVIDER: S-EPMC8379189 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

Gonzalez-Rellan Maria J MJ Fondevila Marcos F MF Fernandez Uxia U Rodríguez Amaia A Varela-Rey Marta M Veyrat-Durebex Christelle C Seoane Samuel S Bernardo Ganeko G Lopitz-Otsoa Fernando F Fernández-Ramos David D Bilbao Jon J Iglesias Cristina C Novoa Eva E Ameneiro Cristina C Senra Ana A Beiroa Daniel D Cuñarro Juan J Dp Chantada-Vazquez Maria M Garcia-Vence Maria M Bravo Susana B SB Da Silva Lima Natalia N Porteiro Begoña B Carneiro Carmen C Vidal Anxo A Tovar Sulay S Müller Timo D TD Ferno Johan J Guallar Diana D Fidalgo Miguel M Sabio Guadalupe G Herzig Stephan S Yang Won Ho WH Cho Jin Won JW Martinez-Chantar Maria Luz ML Perez-Fernandez Roman R López Miguel M Dieguez Carlos C Mato Jose M JM Millet Oscar O Coppari Roberto R Woodhoo Ashwin A Fruhbeck Gema G Nogueiras Ruben R

Nature communications 20210820 1

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 t ...[more]

PMID: 34417460

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O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

Publications

O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

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