P53 involvement in the pathogenesis of fatty liver disease
P53 involvement in the pathogenesis of fatty liver disease
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DOI：
10.1074/jbc.m400884200
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发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Yahagi, N;Shimano, H;Yamada, N
肥胖是工业化社会的主要健康问题，脂肪肝（肝脂肪变性）在肥胖个体中很常见。氧化应激源于细胞内脂肪酸水平的增加，已被认为是脂肪变性肝细胞损伤的原因，尽管确切的机制仍有待阐明。p53，作为一种肿瘤抑制因子而广为人知，已经显示在应激细胞中经常被激活，诱导细胞周期停滞或死亡。在这里，我们证明，p53参与了与脂肪变性相关的肝细胞损伤的分子机制。我们发现，p53在细胞核中的诱导在肝脏中的两个小鼠模型的脂肪肝疾病，ob/ob和一个转基因小鼠模型，过度表达的活性形式的固醇调节元件结合蛋白-1（TgSREBP-1），一个肥胖和其他没有肥胖。p53通路的这种激活导致p21 mRNA表达的升高，这可以被认为是p53活性的指标，因为通过靶向基因破坏产生的缺乏p53的ob/ob小鼠表现出p21升高完全恢复到野生型水平。与这些结果一致，在ob/ob小鼠中Srebp-1基因破坏引起的肝脂肪变性的改善以甘油三酯含量依赖性方式降低了p21表达。此外，在ob/ob小鼠中p53缺陷导致血浆丙氨酸氨基转移酶水平的显著改善，表明p53参与肝细胞损伤的机制。总之，我们揭示了p53在脂肪肝的发病机制中起着重要作用。
Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.