O-GlcNAcylated p53 in the liver modulates hepatic glucose production

被引：52

作者：

Gonzalez-Rellan, Maria J. ^{[1
,2
]}

Fondevila, Marcos F. ^{[1
,2
]}

Fernandez, Uxia ^{[1
,2
]}

Rodriguez, Amaia ^{[2
,3
,4
]}

Varela-Rey, Marta ^{[5
,6
]}

Veyrat-Durebex, Christelle ^{[7
,8
]}

Seoane, Samuel ^{[1
]}

Bernardo, Ganeko ^{[9
,10
]}

Lopitz-Otsoa, Fernando ^{[9
]}

Fernandez-Ramos, David ^{[6
,9
]}

Bilbao, Jon ^{[9
]}

Iglesias, Cristina ^{[1
]}

Novoa, Eva ^{[1
]}

Ameneiro, Cristina ^{[1
]}

Senra, Ana ^{[1
]}

Beiroa, Daniel ^{[1
]}

Cunarro, Juan ^{[1
]}

Chantada-Vazquez, Maria D. P. ^{[11
]}

Garcia-Vence, Maria ^{[11
]}

Bravo, Susana B. ^{[11
]}

Da Silva Lima, Natalia ^{[1
]}

Porteiro, Begona ^{[1
]}

Carneiro, Carmen ^{[1
]}

Vidal, Anxo ^{[1
]}

Tovar, Sulay ^{[1
]}

Muller, Timo D. ^{[12
,13
,14
]}

Ferno, Johan ^{[15
]}

Guallar, Diana ^{[1
]}

Fidalgo, Miguel ^{[1
]}

Sabio, Guadalupe ^{[16
]}

Herzig, Stephan ^{[17
,18
]}

Yang, Won Ho ^{[19
]}

Cho, Jin Won ^{[19
]}

Luz Martinez-Chantar, Maria ^{[5
]}

Perez-Fernandez, Roman ^{[1
]}

Lopez, Miguel ^{[1
]}

Dieguez, Carlos ^{[1
]}

Mato, Jose M. ^{[7
,8
,10
]}

Millet, Oscar ^{[7
,9
]}

Coppari, Roberto ^{[6
]}

Woodhoo, Ashwin ^{[20
,21
,22
,23
]}

Fruhbeck, Gema ^{[2
,3
,4
]}

Nogueiras, Ruben ^{[1
,2
,23
]}

机构：

[1] Univ Santiago de Compostela, CIMUS, Inst Invest Sanitaria, Santiago De Compostela, Spain

[2] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain

[3] Clin Univ Navarra, Metab Res Lab, Pamplona, Spain

[4] IdiSNA, Pamplona, Spain

[5] Basque Res & Technol Alliance BRTA, Liver Dis Lab, Ctr Cooperat Res Biosci CIC BioGUNE, Bizkaia Technol Pk, Derio, Spain

[6] Inst Salud Carlos III, CIBERehd, Madrid, Spain

[7] Univ Geneva, Fac Med, Dept Cell Physiol & Metab, Geneva, Switzerland

[8] Univ Geneva, Fac Med, Diabet Ctr, Geneva, Switzerland

[9] Basque Res & Technol Alliance, Precis Med & Metab Lab, CIC BioGUNE, Derio, Spain

[10] ATLAS Mol Pharma SL, Derio, Spain

[11] Hlth Res Inst Santiago de Compostela IDIS, Prote Unit, Santiago De Compostela, Coruna, Spain

[12] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth GmbH, Helmholtz Diabet Ctr HDC, Inst Diabet & Obes, Oberschleissheim, Germany

[13] German Ctr Diabet Res DZD, Oberschleissheim, Germany

[14] Eberhard Karls Univ Hosp & Clin, Inst Expt & Clin Pharmacol & Pharmacogen, Dept Pharmacol Expt Therapy & Toxicol, Tubingen, Germany

[15] Haukeland Hosp, Hormone Lab, Bergen, Norway

[16] Ctr Nacl Invest Cardiovasc CNIC, Madrid, Spain

[17] Helmholtz Ctr Munich, Inst Diabet & Canc IDC, Neuherberg, Germany

[18] Helmholtz Ctr Munich, Joint Heidelberg IDC Translat Diabet Program, Neuherberg, Germany

[19] Yonsei Univ, Dept Syst Biol, Seoul, South Korea

[20] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[21] Univ Santigo de Compostela, CIMUS, Inst Invest Sanitaria, Santiago De Compostela, Spain

[22] Basque Res & Technol Alliance BRTA, Ctr Cooperat Res Biosci CIC BioGUNE, Nerve Disorder Lab, Bizkaia Technol Pk, Derio, Spain

[23] Galician Agcy Innovat GAIN, Santiago De Compostela, Spain

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

欧盟地平线“2020”; 新加坡国家研究基金会;

关键词：

PHOSPHOENOLPYRUVATE CARBOXYKINASE; INSULIN SENSITIVITY; UP-REGULATION; METABOLISM; ACTIVATION; GENE; GLUCONEOGENESIS; TRANSCRIPTION; INFLAMMATION; TRANSFERASE;

D O I：

10.1038/s41467-021-25390-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

p53 regulates signalling pathways involved in metabolic homeostasis. Here the authors show that O-GlcNAcylation of p53 in the liver plays a key role in the physiological regulation of glucose homeostasis, potentially via controlling the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. 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.

引用

页数：21

共 71 条

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