Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis.
The ability to adapt cellular metabolism to nutrient availability is critical for survival. The liver plays a central role in the adaptation to starvation by switching from glucose-consuming processes and lipid synthesis to providing energy substrates like glucose to the organism. Here we report a previously unrecognized role of the tumor suppressor p53 in the physiologic adaptation to food withdrawal. We found that starvation robustly increases p53 protein in mouse liver. This induction was posttranscriptional and mediated by a hepatocyte-autonomous and AMP-activated protein kinase-dependent mechanism. p53 stabilization was required for the adaptive expression of genes involved in amino acid catabolism. Indeed, acute deletion of p53 in livers of adult mice impaired hepatic glycogen storage and induced steatosis. Upon food withdrawal, p53-deleted mice became hypoglycemic and showed defects in the starvation-associated utilization of hepatic amino acids. In summary, we provide novel evidence for a p53-dependent integration of acute changes of cellular energy status and the metabolic adaptation to starvation. Because of its tumor suppressor function, p53 stabilization by starvation could have implications for both metabolic and oncological diseases of the liver.-Prokesch, A., Graef, F. A., Madl, T., Kahlhofer, J., Heidenreich, S., Schumann, A., Moyschewitz, E., Pristoynik, P., Blaschitz, A., Knauer, M., Muenzner, M., Bogner-Strauss, J. G., Dohr, G., Schulz, T. J., Schupp, M. Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis.
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria; andreas.prokesch@medunigraz.at.
Andreas
A
Prokesch
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
Franziska A
FA
Graef
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
Tobias
T
Madl
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria.
Jennifer
J
Kahlhofer
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
Steffi
S
Heidenreich
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
Anne
A
Schumann
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria.
Elisabeth
E
Moyschewitz
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria.
Petra
P
Pristoynik
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria.
Astrid
A
Blaschitz
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
Miriam
M
Knauer
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
Matthias
M
Muenzner
Institute of Biochemistry, Graz University of Technology, Graz, Austria.
Juliane G
JG
Bogner-Strauss
Institute of Cell Biology, Histology, and Embryology, Medical University Graz, Graz, Austria.
Gottfried
G
Dohr
Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany; and.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
Tim J
TJ
Schulz
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany; michael.schupp@charite.de.
Michael
M
Schupp
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005234:Fatty Liver / Q000378:metabolism; D005508:Food Deprivation / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006003:Glycogen / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D006003:Glycogen; D000263:Adenylate Kinase
AMPK; fasting; hepatic steatosis; liver metabolism; nutrient deprivation