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p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine

1
Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, 8010 Graz, Austria
2
Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehhbrücke, 14558 Nuthetal, Germany
3
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
4
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
5
Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, 10117 Berlin, Germany
6
BioTechMed-Graz, 8010 Graz, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(3), 921; https://doi.org/10.3390/ijms19030921
Received: 7 February 2018 / Revised: 16 March 2018 / Accepted: 17 March 2018 / Published: 20 March 2018
(This article belongs to the Collection Molecular Mechanisms of Human Liver Diseases)
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC. View Full-Text
Keywords: p53; liver disease; insulin resistance; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; hepatocellular carcinoma; liver regeneration; mouse models p53; liver disease; insulin resistance; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; hepatocellular carcinoma; liver regeneration; mouse models
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MDPI and ACS Style

Krstic, J.; Galhuber, M.; Schulz, T.J.; Schupp, M.; Prokesch, A. p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine. Int. J. Mol. Sci. 2018, 19, 921.

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