Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease
Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease
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DOI：
10.1172/jci73957
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Desdouets, Chantal
中科院分区：
文献类型：
--
作者：
Gentric, Geraldine;Maillet, Vanessa;Desdouets, Chantal
多倍化是基因组中可能发生的最引人注目的变化之一。在肝脏中，生理性多倍化事件发生在肝脏发育期间和整个成年生活期间。在这里，我们确定了非酒精性脂肪性肝病（NAFLD）中发生的病理性多倍化，NAFLD是一种广泛的肝脏代谢紊乱，被认为是肝细胞癌（HCC）的危险因素。在NAFLD小鼠模型中，脂肪肝实质显示出多倍体化过程的改变，包括存在大比例的高度多倍体单核细胞，这在正常肝实质中很少观察到。非酒精性脂肪性肝炎（NASH）患者的活组织检查显示，与对照组相比，肝细胞倍性存在改变。来自NAFLD小鼠的肝细胞显示通过细胞周期的S/G（2）期的进展是低效的。这种改变与G（2）/M DNA损伤检查点的激活有关，该检查点阻止了细胞周期蛋白B1/CDK 1复合物的激活。此外，我们确定氧化应激促进高度多倍体细胞的出现，抗氧化剂处理的NAFLD肝细胞恢复正常细胞分裂并恢复到多倍体的生理状态。总的来说，这些发现表明氧化应激促进病理性多倍化，并表明这是NAFLD的早期事件，可能有助于HCC的发展。
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/G(2) phases of the cell cycle was inefficient. This alteration was associated with activation of a G(2)/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.