Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease
Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease
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DOI：
10.1016/s0002-9440(10)63489-x
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Diehl, AM
中科院分区：
文献类型：
--
作者：
Roskams, T;Yang, SQ;Diehl, AM
在动物中，氧化性肝损伤和肝细胞增殖抑制的组合增加了肝祖细胞（卵圆细胞）的数量。我们研究了不同的脂肪性肝病小鼠模型和非酒精性脂肪性肝病或酒精性肝病患者，以确定脂肪肝中卵圆细胞是否增加，并阐明这种反应的机制。在不同程度上，所有的小鼠模型表现出过量的肝线粒体产生H2 O2，一种已知的诱导细胞周期抑制剂。在具有最大H2 O2产生的小鼠中，成熟肝细胞增殖受到最大抑制，并且卵圆细胞积累的数量最多。这些细胞在再生激发后分化成中间肝细胞样细胞。非酒精性脂肪性肝病和酒精性肝病患者的肝卵圆细胞也显著增加。在人类中，纤维化阶段和卵圆细胞数量以及中间肝细胞样细胞的数量密切相关。然而，肝硬化并不是这两个物种卵圆细胞积聚所必需的。相反，在小鼠中，人类脂肪肝疾病中的祖细胞活化与成熟肝细胞的复制抑制有关。在脂肪肝疾病期间祖细胞的激活可能增加肝细胞癌的风险，类似于在大鼠肝癌发生的Solt-Farber模型中观察到的。
in animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H2O2, a known inducer of cell-cycle inhibitors. in mice with the greatest H2O2 production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Solt-Farber model of hepatocarcinogenesis in rats.