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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia
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Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia

机译：Nrf1基因在成年小鼠中的肝脏特异性失活导致非酒精性脂肪性肝炎和肝肿瘤

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Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrfl in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid ho-meostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.
机译：敲除研究表明，转录因子Nrf1对胚胎发育至关重要。 Nrf1被暗示在通过抗氧化反应元件（ARE）介导氧化应激反应基因的激活中发挥作用。由于基因敲除小鼠具有胚胎致死性，因此无法分析成年基因敲除小鼠的这一功能。我们在这里报告说，nrfl在体细胞中失活的小鼠肝脏发生了肝癌。在癌症发展之前，突变肝表现出脂肪变性，凋亡，坏死，炎症和纤维化。此外，缺乏Nrf1的肝细胞表现出氧化应激，基因表达分析显示各种含有ARE的基因表达降低，而CYP4A基因上调。这些结果表明，由CYP4A介导的脂肪酸氧化产生的活性氧与ARE响应基因的表达减少协同作用，从而在突变型肝细胞中引起氧化应激。因此，Nrf1具有抗氧化应激的保护功能，并可能具有肝脏脂质脂质稳态的功能。由于该表型与非酒精性脂肪性肝炎相似，因此这些动物可被用作研究非酒精性脂肪性肝炎和肝癌的分子机制的模型。

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