title: 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.forename: Géraldine
authors.initials: G
authors.lastname: Gentric
authors.forename: Vanessa
authors.initials: V
authors.lastname: Maillet
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Dominique
authors.initials: D
authors.lastname: Couton
authors.forename: Antoine
authors.initials: A
authors.lastname: L'Hermitte
authors.forename: Ganna
authors.initials: G
authors.lastname: Panasyuk
authors.forename: Bernard
authors.initials: B
authors.lastname: Fromenty
authors.forename: Séverine
authors.initials: S
authors.lastname: Celton-Morizur
authors.forename: Chantal
authors.initials: C
authors.lastname: Desdouets
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D059305:Diet, High-Fat / Q000009:adverse effects; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D011123:Polyploidy; D012307:Risk Factors