Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis

Abstract

The ability to adapt cellularmetabolism 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 foodwithdrawal. We found that starvation robustly increases p53 protein inmouse liver. This induction was posttranscriptional and mediated by a hepatocyte-autonomous and AMP-activated protein kinase-dependentmechanism.p53stabilizationwas required for the adaptiveexpressionofgenes involvedinaminoacid catabolism. Indeed, acute deletion of p53 in livers of adultmice 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 bothmetabolic 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.Liverp53is stabilizeduponstarvation and required for amino acid catabolismand gluconeogenesis.