ECE2021 Oral Communications Oral Communications 7: Diabetes, Obesity, Metabolism and Nutrition (6 abstracts)
Hepatic O-GlcNAcylated-p53 as a hub integrating the glucose counterregulatory response and insulin-suppressed gluconeogenesis
María Jesús González Rellán 1 , Marcos Fernández Fondevila 1 , Uxia Fernández Paz 1 , Amaia Rodríguez 2 , Marta Varela Rey 3 , Christelle Veyrat-Durebex 4 , Samuel Seoane 1 , Ganeko Bernardo 3 , Fernando Lopitz Otsoa 3 , David Fernandez Ramos 3 , Jon Bilbao 3 , Cristina Iglesias 1 , Timo D Müller 5 , Stephan Herzig 5 , Maria Luz Martinez Chantar 3 , Roman Perez Fernandez 1 , Miguel Lopez 1 , Carlos Diéguez 1 , Jose Maria Mato 3 , Oscar Millet 3 , Roberto Coppari 4 , Ashwin Woodhoo 3 , Gema Fruhbeck 2 & Rubén Nogueiras Pozo 1
1CIMUS, Physiology, Santiago de Compostela, Spain; 2Clínica Universidad de Navarra, Metabolic Research Laboratory, Pamplona, Spain; 3CIC Biogune, Bilbao, Spain; 4University of Geneva, Department of cell physiology and metabolim, Geneva, Switzerland; 5Helmholtz Zentrum München, München, Germany
Background and aims
Glucose homeostasis is essential for life. The liver is among the key tissues for maintaining an adequate metabolic homeostasis and its alterations are at the root of the pathogenesis of many disease states. A perfect balance between glucose production, mainly at the liver, and glucose consumption in different tissues, is provided by the action of insulin and counterregulatory hormones as glucagon, cortisol or catecholamines. There is nowadays growing evidence demonstrating that cell cycle regulators have important actions in the metabolic control. In cancer cells, p53 regulates glucose metabolism, opposing the Warburg effect. Nevertheless, the relevance of endogenous hepatic p53 in the physiological fluctuation of gluconeogenesis, as well as the molecular pathways mediating these effects, remains totally unknown.
Method
Either wild type (WT) mice or hepatic p53-deficient littermates were subjected to different nutritional conditions to evaluate p53 expression and function. These experiments were also performed in vitro, in both THLE-2 cells and HEP3B cells (a hepatic KOp53 cell line). PTT, Gly, GTT and ITT were performed to study glucose homeostasis in WT mice and p53-deficient mice, as well as a clamp to further test their gluconeogenic capacity. Gain-of-function experiments were also performed, over-expressing p53 in the liver. In vitro and in vivo models were treated with gluconeogenic hormones and insulin, to study the role and function of p53 mediating their hepatic actions. Mutagenesis experiments were also performed to evaluate the relevance of O-GlcNAcylation on p53 gluconeogenic actions.
Results
We show that upon starvation hepatic p53 is stabilized by O-GlcNAcylation, and plays an essential role in the physiological regulation of glucose homeostasis. p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mutant p53 that cannot be O-GlcNAcylated is unable to promote PCK1 activity gluconeogenesis. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augmented protein levels of p53, and administration of these hormones to 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 T2D patients, and positively correlate with glucose and HOMA-IR.
Conclusion
Our results indicate that O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis, with a potential therapeutic target interest.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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