Sladky Valentina C, Eichin Felix, Reiberger Thomas, Villunger Andreas
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
J Hepatol. 2021 Nov;75(5):1177-1191. doi: 10.1016/j.jhep.2021.06.030. Epub 2021 Jul 3.
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 hepatocyte ploidy on 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. Herein, we discuss the molecular mechanisms regulating hepatocyte polyploidisation and its implication for different liver diseases and hepatocellular carcinoma. We report on centrosomes' role in limiting polyploidy by activating the p53 signalling network (via the PIDDosome multiprotein complex) and we discuss the role of this pathway in liver disease. Increased hepatocyte ploidy is a hallmark of hepatic inflammation and may play a protective role against liver cancer. Our evolving understanding of hepatocyte ploidy is discussed from the perspective of its potential clinical application for risk stratification, prognosis, and novel therapeutic strategies in liver disease and hepatocellular carcinoma.
在一些人类细胞类型中观察到DNA含量（倍性）的平衡增加，包括骨吸收破骨细胞、产生血小板的巨核细胞、心肌细胞或肝细胞。肝细胞倍性增加对正常生理和多种肝脏疾病的影响仍知之甚少。最近的研究结果表明，对肝毒性应激的快速遗传适应以及对恶性转化的保护是有益的作用。在此，我们讨论调节肝细胞多倍体化的分子机制及其对不同肝脏疾病和肝细胞癌的影响。我们报告了中心体通过激活p53信号网络（通过PIDDosome多蛋白复合物）在限制多倍体中的作用，并讨论了该途径在肝脏疾病中的作用。肝细胞倍性增加是肝脏炎症的一个标志，可能对肝癌起到保护作用。我们从肝细胞倍性在肝脏疾病和肝细胞癌的风险分层、预后及新型治疗策略中的潜在临床应用角度，讨论了我们对其不断发展的认识。
