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Polyploidy control in hepatic health and disease
J Hepatol. 2021 Jul 3;S0168-8278(21)01879-1. doi: 10.1016/j.jhep.2021.06.030.Online ahead of print.
Valentina C Sladky1, Felix Eichin2, Thomas Reiberger3, Andreas Villunger4
1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, AT.
3Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AT; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, AT; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, AT.
4Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, AT; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, AT; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, AT. Electronic address: email@example.com.
A balanced increase in DNA-content (ploidy) is observed in some human cell types, including bone-resorbing osteoclasts, platelet-producing megakaryocytes, cardiomyocytes or hepatocytes. The impact of increased ploidy in hepatocytes for normal physiology and diverse liver pathologies is still poorly understood. Recent findings suggest swift genetic adaptation to hepatotoxic stress and the protection from malignant transformation as beneficial effects. Here, we discuss the molecular mechanisms regulating hepatocyte polyploidization in its implication for different liver diseases and hepatocellular carcinoma (HCC). We report on the role of centrosomes as critical structures activating the p53 signaling network via the PIDDosome multi-protein complex to limit polyploidy and the implication of this pathway for liver disease. Increased hepatocyte ploidy is a hallmark of hepatic inflammation and may play a protective role against liver cancer. The evolving knowledge on hepatocyte ploidy is discussed in perspective of potential clinical application for risk stratification, prognosis, and novel therapeutic strategies in liver disease and HCC.