Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease
Géraldine Gentric, … , Séverine Celton-Morizur, Chantal Desdouets
Géraldine Gentric, … , Séverine Celton-Morizur, Chantal Desdouets
Published March 2, 2015; First published January 26, 2015
Citation Information: J Clin Invest. 2015;125(3):981-992. https://doi.org/10.1172/JCI73957.
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Categories: Research Article Hepatology

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

Abstract

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.

Authors

Géraldine Gentric, Vanessa Maillet, Valérie Paradis, Dominique Couton, Antoine L’Hermitte, Ganna Panasyuk, Bernard Fromenty, Séverine Celton-Morizur, Chantal Desdouets

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Figure 1

Hepatocyte ploidy profiles are altered in a genetic mouse model of NAFLD.

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Hepatocyte ploidy profiles are altered in a genetic mouse model of NAFLD...
(A) Hepatocytes from WT and ob/ob livers were separated into ploidy populations by FACS analyses (n = 3 per group) with 2c, 4c, and 8c and >8c DNA content corresponding to diploid, tetraploid, and highly polyploid hepatocytes, respectively. Of note, smear between hepatocytes populations (ob/ob cells) is due to high granularity (correlation with high lipid content). 7AAD, 7-aminoactinomycin D. (B) Images of liver sections from WT and ob/ob mice after double staining with β-catenin (plasma membrane labeling, red) and Hoechst (nucleus, green) (scale bar: 20 μm). Percentage of binuclear hepatocytes in WT and ob/ob mice (n = 6 per group). Results represent mean ± SEM. ***P < 0.001, Student’s t test. (C) β-Catenin/Hoechst immunostaining in WT and ob/ob mice (scale bar: 20 μm) and box plots of the percentage of 2n, 4n, and ≥8n mononuclear hepatocytes relative to total hepatocytes in WT and ob/ob mice. The bottom, central, and top lines of each box represent the first quartile, median, and third quartile of the distribution, respectively (n = 6 per group). **P < 0.005, ***P < 0.001, Student’s t test.