[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.4062/biomolther.2022.070

Polyploidization of Hepatocytes: Insights into the Pathogenesis of Liver Diseases

Kim, Ju-Yeon (College of Pharmacy, Seoul National University)
Choi, Haena (College of Pharmacy, Seoul National University)
Kim, Hyeon-Ji (College of Pharmacy, Seoul National University)
Jee, Yelin (College of Pharmacy, Seoul National University)
Noh, Minsoo (College of Pharmacy, Seoul National University)
Lee, Mi-Ock (College of Pharmacy, Seoul National University)

Publication Information

Biomolecules & Therapeutics / v.30, no.5, 2022 , pp. 391-398 More about this Journal

Abstract

Polyploidization is a process by which cells are induced to possess more than two sets of chromosomes. Although polyploidization is not frequent in mammals, it is closely associated with development and differentiation of specific tissues and organs. The liver is one of the mammalian organs that displays ploidy dynamics in physiological homeostasis during its development. The ratio of polyploid hepatocytes increases significantly in response to hepatic injury from aging, viral infection, iron overload, surgical resection, or metabolic overload, such as that from non-alcoholic fatty liver diseases (NAFLDs). One of the unique features of NAFLD is the marked heterogeneity of hepatocyte nuclear size, which is strongly associated with an adverse liver-related outcome, such as hepatocellular carcinoma, liver transplantation, and liver-related death. Thus, hepatic polyploidization has been suggested as a potential driver in the progression of NAFLDs that are involved in the control of the multiple pathogenicity of the diseases. However, the importance of polyploidy in diverse pathophysiological contexts remains elusive. Recently, several studies reported successful improvement of symptoms of NAFLDs by reducing pathological polyploidy or by controlling cell cycle progression in animal models, suggesting that better understanding the mechanisms of pathological hepatic polyploidy may provide insights into the treatment of hepatic disorders.

Keywords

Polyploidization; Hepatocytes; NAFLD; HCC;

Citations & Related Records

Times Cited By KSCI : 2 (Citation Analysis)

Reference
Cited By KSCI

1	Nakajima, T., Nakashima, T., Okada, Y., Jo, M., Nishikawa, T., Mitsumoto, Y., Katagishi, T., Kimura, H., Itoh, Y., Kagawa, K. and Yoshikawa, T. (2010) Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: comparison with telomere-specific quantitative FISH and p21 immunohistochemistry. Pathol. Int. 60, 175-183. DOI
2	Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. V., McCullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. and Doo, E.; NASH Clinical Research Network (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956-965. DOI
3	Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., Grellscheid, S. N., Hoeijmakers, J. H. J., Barnhoorn, S., Mann, D. A., Bird, T. G., Vermeij, W. P., Kirkland, J. L., Passos, J. F., von Zglinicki, T. and Jurk, D. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691.
4	Ow, J. R., Caldez, M. J., Zafer, G., Foo, J. C., Li, H. Y., Ghosh, S., Wollmann, H., Cazenave-Gassiot, A., Ong, C. B., Wenk, M. R., Han, W., Choi, H. and Kaldis, P. (2020) Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division. Elife 9, e63835.
5	Pandit, S. K., Westendorp, B. and de Bruin, A. (2013) Physiological significance of polyploidization in mammalian cells. Trends Cell Biol. 23, 556-566. DOI
6	Radziejwoski, A., Vlieghe, K., Lammens, T., Berckmans, B., Maes, S., Jansen, M. A., Knappe, C., Albert, A., Seidlitz, H. K., Bahnweg, G., Inze, D. and De Veylder, L. (2011) Atypical E2F activity coordinates PHR1 photolyase gene transcription with endoreduplication onset. EMBO J. 30, 355-363. DOI
7	Pandit, S. K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C., Cornelissen, P. W., Toussaint, M. J., Lamers, W. H. and de Bruin, A. (2012) E2F8 is essential for polyploidization in mammalian cells. Nat. Cell Biol. 14, 1181-1191. DOI
8	Peng, C., Stewart, A. G., Woodman, O. L., Ritchie, R. H. and Qin, C. X. (2020) Non-alcoholic steatohepatitis: a review of its mechanism, models and medical treatments. Front. Pharmacol. 11, 603926.
9	Shimada, Y., Kuninaga, S., Ariyoshi, M., Zhang, B., Shiina, Y., Takahashi, Y., Umemoto, N., Nishimura, Y., Enari, H. and Tanaka, T. (2015) E2F8 promotes hepatic steatosis through FABP3 expression in diet-induced obesity in zebrafish. Nutr. Metab. 12, 17.
10	Sher, N., Von Stetina, J. R., Bell, G. W., Matsuura, S., Ravid, K. and Orr-Weaver, T. L. (2013) Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells. Proc. Natl. Acad. Sci. U.S.A. 110, 9368-9373. DOI
11	So, J., Kim, A., Lee, S. H. and Shin, D. (2020) Liver progenitor cell-driven liver regeneration. Exp. Mol. Med. 52, 1230-1238. DOI
12	Ullah, Z., Kohn, M. J., Yagi, R., Vassilev, L. T. and DePamphilis, M. L. (2008) Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes Dev. 22, 3024-3036. DOI
13	Wang, M. J., Chen, F., Lau, J. T. Y. and Hu, Y. P. (2017) Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis. 8, e2805.
14	Wang, N., Hao, F., Shi, Y. and Wang, J. (2021) The controversial role of polyploidy in hepatocellular carcinoma. OncoTargets Ther. 14, 5335-5344. DOI
15	Troadec, M.-B., Courselaud, B., Detivaud, L., Haziza-Pigeon, C., Leroyer, P., Brissot, P. and Loreal, O. (2006) Iron overload promotes Cyclin D1 expression and alters cell cycle in mouse hepatocytes. J. Hepatol. 44, 391-399. DOI
16	Zhang, S., Chen, Q., Liu, Q., Li, Y., Sun, X., Hong, L., Ji, S., Liu, C., Geng, J., Zhang, W., Lu, Z., Yin, Z. Y., Zeng, Y., Lin, K. H., Wu, Q., Li, Q., Nakayama, K., Nakayama, K. I., Deng, X., Johnson, R. L., Zhu, L., Gao, D., Chen, L. and Zhou, D. (2017) Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2. Cancer Cell 31, 669-684.e7. DOI
17	Zhang, S., Nguyen, L. H., Zhou, K., Tu, H. C., Sehgal, A., Nassour, I., Li, L., Gopal, P., Goodman, J., Singal, A. G., Yopp, A., Zhang, Y., Siegwart, D. J. and Zhu, H. (2018) Knockdown of anillin actin binding protein blocks cytokinesis in hepatocytes and reduces liver tumor development in mice without affecting regeneration. Gastroenterology 154, 1421-1434. DOI
18	Ahodantin, J., Bou-Nader, M., Cordier, C., Megret, J., Soussan, P., Desdouets, C. and Kremsdorf, D. (2019) Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation. Oncogene 38, 2645-2657. DOI
19	Anatskaya, O. V. and Vinogradov, A. E. (2007) Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver. Genomics 89, 70-80. DOI
20	Wang, M.-J., Chen, F., Li, J.-X., Liu, C.-C., Zhang, H.-B., Xia, Y., Yu, B., You, P., Xiang, D., Lu, L., Yao, H., Borjigin, U., Yang, G.-S., Wangensteen, K. J., He, Z.-Y., Wang, X. and Hu, Y.-P. (2014) Reversal of hepatocyte senescence after continuous in vivo cell proliferation. Hepatology 60, 349-361. DOI
21	Watanabe, T. and Tanaka, Y. (1982) Age-related alterations in the size of human hepatocytes. A study of mononuclear and binucleate cells. Virchows Archiv. B 39, 9-20. DOI
22	Wertheim, B., Beukeboom, L. W. and van de Zande, L. (2013) Polyploidy in animals: effects of gene expression on sex determination, evolution and ecology. Cytogenet. Genome Res. 140, 256-269. DOI
23	Wilkinson, P. D., Delgado, E. R., Alencastro, F., Leek, M. P., Roy, N., Weirich, M. P., Stahl, E. C., Otero, P. A., Chen, M. I., Brown, W. K. and Duncan, A. W. (2019) The polyploid state restricts hepatocyte proliferation and liver regeneration in mice. Hepatology 69, 1242-1258. DOI
24	Benedict, M. and Zhang, X. (2017) Non-alcoholic fatty liver disease: an expanded review. World J. Hepatol. 9, 715-732. DOI
25	Anatskaya, O. V. and Vinogradov, A. E. (2010) Somatic polyploidy promotes cell function under stress and energy depletion: evidence from tissue-specific mammal transcriptome. Funct. Integr. Genomics 10, 433-446. DOI
26	Aravinthan, A., Scarpini, C., Tachtatzis, P., Verma, S., Penrhyn-Lowe, S., Harvey, R., Davies, S. E., Allison, M., Coleman, N. and Alexander, G. (2013) Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J. Hepatol. 58, 549-556. DOI
27	Yamada, T., Sogawa, K., Kim, J. K., Izumi, K., Suzuki, Y., Muramatsu, Y., Sumida, T., Hamakawa, H. and Matsumoto, K. (1998) Increased polyploidy, delayed mitosis and reduced protein phosphatase-1 activity associated with excess copper in the long evans cinnamon rat. Res. Commun. Mol. Pathol. Pharmacol. 99, 283-304.
28	Bonkovsky, H. L. (1991) Iron and the liver. Am. J. Med. Sci. 301, 32-43. DOI
29	Bou-Nader, M., Caruso, S., Donne, R., Celton-Morizur, S., Calderaro, J., Gentric, G., Cadoux, M., L'Hermitte, A., Klein, C., Guilbert, T., Albuquerque, M., Couchy, G., Paradis, V., Couty, J. P., Zucman-Rossi, J. and Desdouets, C. (2020) Polyploidy spectrum: a new marker in HCC classification. Gut 69, 355-364. DOI
30	Cao, J., Wang, J., Jackman, C. P., Cox, A. H., Trembley, M. A., Balowski, J. J., Cox, B. D., De Simone, A., Dickson, A. L., Di Talia, S., Small, E. M., Kiehart, D. P., Bursac, N. and Poss, K. D. (2017) Tension creates an endoreplication wavefront that leads regeneration of epicardial tissue. Dev. Cell 42, 600-615.e4. DOI
31	Mantovani, A. and Dalbeni, A. (2021) Treatments for NAFLD: state of art. Int. J. Mol. Sci. 22, 2350.
32	Li, X., Liu, L., Li, R., Wu, A., Lu, J., Wu, Q., Jia, J., Zhao, M. and Song, H. (2018) Hepatic loss of Lissencephaly 1 (Lis1) induces fatty liver and accelerates liver tumorigenesis in mice. J. Biol. Chem. 293, 5160-5171. DOI
33	Loomba, R., Friedman, S. L. and Shulman, G. I. (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537-2564. DOI
34	Machida, K., Liu, J. C., McNamara, G., Levine, A., Duan, L. and Lai, M. M. (2009) Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway. J. Virol. 83, 12590-12600. DOI
35	Martins, P. N. A., Theruvath, T. P. and Neuhaus, P. (2008) Rodent models of partial hepatectomies. Liver Int. 28, 3-11.
36	Donne, R., Saroul-Ainama, M., Cordier, P., Celton-Morizur, S. and Desdouets, C. (2020) Polyploidy in liver development, homeostasis and disease. Nat. Rev. Gastroenterol. Hepatol. 17, 391-405. DOI
37	Michalopoulos, G. K. and DeFrances, M. C. (1997) Liver regeneration. Science 276, 60-66. DOI
38	Miettinen, T. P., Pessa, H. K., Caldez, M. J., Fuhrer, T., Diril, M. K., Sauer, U., Kaldis, P. and Bjorklund, M. (2014) Identification of transcriptional and metabolic programs related to mammalian cell size. Curr. Biol. 24, 598-608. DOI
39	Diril, M. K., Ratnacaram, C. K., Padmakumar, V. C., Du, T., Wasser, M., Coppola, V., Tessarollo, L. and Kaldis, P. (2012) Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proc. Natl. Acad. Sci. U.S.A. 109, 3826-3831. DOI
40	Fox, D. T. and Duronio, R. J. (2013) Endoreplication and polyploidy: insights into development and disease. Development 140, 3-12. DOI
41	Muramatsu, Y., Yamada, T., Moralejo, D. H., Mochizuki, H., Sogawa, K. and Matsumoto, K. (2000) Increased polyploid incidence is associated with abnormal copper accumulation in the liver of LEC mutant rat. Res. Commun. Mol. Pathol. Pharmacol. 107, 129-136.
42	Hsu, S. H., Delgado, E. R., Otero, P. A., Teng, K. Y., Kutay, H., Meehan, K. M., Moroney, J. B., Monga, J. K., Hand, N. J., Friedman, J. R., Ghoshal, K. and Duncan, A. W. (2016) MicroRNA-122 regulates polyploidization in the murine liver. Hepatology 64, 599-615. DOI
43	Gentric, G. and Desdouets, C. (2014) Polyploidization in liver tissue. Am. J. Pathol. 184, 322-331. DOI
44	Hixon, M. L. and Gualberto, A. (2003) Vascular smooth muscle polyploidization--from mitotic checkpoints to hypertension. Cell Cycle 2, 105-110. DOI
45	Cast, A., Kumbaji, M., D'Souza, A., Rodriguez, K., Gupta, A., Karns, R., Timchenko, L. and Timchenko, N. (2019) Liver proliferation is an essential driver of fibrosis in mouse models of nonalcoholic fatty liver disease. Hepatol. Commun. 3, 1036-1049. DOI
46	Celton-Morizur, S., Merlen, G., Couton, D. and Desdouets, C. (2010) Polyploidy and liver proliferation: central role of insulin signaling. Cell Cycle 9, 460-466. DOI
47	Gentric, G., Maillet, V., Paradis, V., Couton, D., L'Hermitte, A., Panasyuk, G., Fromenty, B., Celton-Morizur, S. and Desdouets, C. (2015) Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J. Clin. Invest. 125, 981-992. DOI
48	Hardy, T., Oakley, F., Anstee, Q. M. and Day, C. P. (2016) Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu. Rev. Pathol. 11, 451-496. DOI
49	Hino, K., Yanatori, I., Hara, Y. and Nishina, S. (2021) Iron and liver cancer: an inseparable connection. FEBS J. doi: 10.1111/febs.16208 [Online ahead of print]. DOI
50	Richter, M. L., Deligiannis, I. K., Yin, K., Danese, A., Lleshi, E., Coupland, P., Vallejos, C. A., Matchett, K. P., Henderson, N. C., Colome-Tatche, M. and Martinez-Jimenez, C. P. (2021) Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. Nat. Commun. 12, 4264.
51	Schwartz-Arad, D., Zajicek, G. and Bartfeld, E. (1989) The streaming liver IV: DNA content of the hepatocyte increases with its age. Liver 9, 93-99. DOI
52	Ratziu, V., Harrison, S. A., Francque, S., Bedossa, P., Lehert, P., Serfaty, L., Romero-Gomez, M., Boursier, J., Abdelmalek, M., Caldwell, S., Drenth, J., Anstee, Q. M., Hum, D., Hanf, R., Roudot, A., Megnien, S., Staels, B. and Sanyal, A.; GOLDEN-505 Investigator Study Group (2016) Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147-1159 e5.
53	Kim, E. J., Yoon, Y. S., Hong, S., Son, H. Y., Na, T. Y., Lee, M. H., Kang, H. J., Park, J., Cho, W. J., Kim, S. G., Koo, S. H., Park, H. G. and Lee, M. O. (2012) Retinoic acid receptor-related orphan receptor alpha-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis. Hepatology 55, 1379-1388. DOI
54	Chen, H. Z., Ouseph, M. M., Li, J., Pecot, T., Chokshi, V., Kent, L., Bae, S., Byrne, M., Duran, C., Comstock, G., Trikha, P., Mair, M., Senapati, S., Martin, C. K., Gandhi, S., Wilson, N., Liu, B., Huang, Y. W., Thompson, J. C., Raman, S., Singh, S., Leone, M., Machiraju, R., Huang, K., Mo, X., Fernandez, S., Kalaszczynska, I., Wolgemuth, D. J., Sicinski, P., Huang, T., Jin, V. and Leone, G. (2012) Canonical and atypical E2Fs regulate the mammalian endocycle. Nat. Cell Biol. 14, 1192-1202. DOI
55	Denechaud, P. D., Lopez-Mejia, I. C., Giralt, A., Lai, Q., Blanchet, E., Delacuisine, B., Nicolay, B. N., Dyson, N. J., Bonner, C., Pattou, F., Annicotte, J. S. and Fajas, L. (2016) E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis. J. Clin. Invest. 126, 137-150.
56	Dewhurst, M. R., Ow, J. R., Zafer, G., van Hul, N. K. M., Wollmann, H., Bisteau, X., Brough, D., Choi, H. and Kaldis, P. (2020) Loss of hepatocyte cell division leads to liver inflammation and fibrosis. PLoS Genet. 16, e1009084.
57	Lammens, T., Li, J., Leone, G. and De Veylder, L. (2009) Atypical E2Fs: new players in the E2F transcription factor family. Trends Cell Biol. 19, 111-118. DOI
58	Lin, H., Huang, Y. S., Fustin, J. M., Doi, M., Chen, H., Lai, H. H., Lin, S. H., Lee, Y. L., King, P. C., Hou, H. S., Chen, H. W., Young, P. Y. and Chao, H. W. (2021) Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nat. Commun. 12, 645.
59	Kew, M. C. (2011) Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J. Gastroenterol. Hepatol. 26 Suppl 1, 144-152. DOI
60	Jin, J., Valanejad, L., Nguyen, T. P., Lewis, K., Wright, M., Cast, A., Stock, L., Timchenko, L. and Timchenko, N. A. (2016) Activation of CDK4 triggers development of non-alcoholic fatty liver disease. Cell Rep. 16, 744-756. DOI
61	Kim, J. Y., Yang, I. S., Kim, H. J., Yoon, J. Y., Han, Y. H., Seong, J. K. and Lee, M. O. (2022) RORα contributes to the maintenance of genome ploidy in the liver of mice with diet-induced nonalcoholic steatohepatitis. Am. J. Physiol. Endocrinol. Metab. 322, E118-E131. DOI
62	Kim, K. H. and Lee, M. S. (2018) Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches. Front. Endocrinol. 9, 485.
63	Kudryavtsev, B. N., Kudryavtseva, M. V., Sakuta, G. A. and Stein, G. I. (1993) Human hepatocyte polyploidization kinetics in the course of life cycle. Virchows Archiv. B 64, 387.
64	Lazzeri, E., Angelotti, M. L., Peired, A., Conte, C., Marschner, J. A., Maggi, L., Mazzinghi, B., Lombardi, D., Melica, M. E., Nardi, S., Ronconi, E., Sisti, A., Antonelli, G., Becherucci, F., De Chiara, L., Guevara, R. R., Burger, A., Schaefer, B., Annunziato, F., Anders, H. J., Lasagni, L. and Romagnani, P. (2018) Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury. Nat. Commun. 9, 1344.
65	Kreutz, C., MacNelly, S., Follo, M., Waldin, A., Binninger-Lacour, P., Timmer, J. and Bartolome-Rodriguez, M. M. (2017) Hepatocyte ploidy is a diversity factor for liver homeostasis. Front. Physiol. 8, 862.
66	Matsumoto, T., Wakefield, L. and Grompe, M. (2021) The significance of polyploid hepatocytes during aging process. Cell. Mol. Gastroenterol. Hepatol. 11, 1347-1349. DOI
67	Madra, S., Styles, J. and Smith, A. G. (1995) Perturbation of hepatocyte nuclear populations induced by iron and polychlorinated biphenyls in C57BL/10ScSn mice during carcinogenesis. Carcinogenesis 16, 719-727. DOI
68	Kim, S. H., Jeon, Y., Kim, H. S., Lee, J. K., Lim, H. J., Kang, D., Cho, H., Park, C. K., Lee, H. and Lee, C. W. (2016) Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase. Hepatology 63, 247-259. DOI
69	Miyaoka, Y., Ebato, K., Kato, H., Arakawa, S., Shimizu, S. and Miyajima, A. (2012) Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr. Biol. 22, 1166-1175. DOI
70	Comai, L. (2005) The advantages and disadvantages of being polyploid. Nat. Rev. Genet. 6, 836-846. DOI
71	Davoli, T. and de Lange, T. (2011) The causes and consequences of polyploidy in normal development and cancer. Annu. Rev. Cell Dev. Biol. 27, 585-610. DOI
72	Dawson, S., Higashitsuji, H., Wilkinson, A. J., Fujita, J. and Mayer, R. J. (2006) Gankyrin: a new oncoprotein and regulator of pRb and p53. Trends Cell Biol. 16, 229-233. DOI