Field of Basic Sports Medicine, Sports Medicine, Faculty of Medicine, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan.
J Gastroenterol. 2012 Aug;47(8):924-35. doi: 10.1007/s00535-012-0552-9. Epub 2012 Feb 28.
The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is a key regulator for induction of hepatic antioxidative stress systems. We aimed to investigate whether activation of Nrf2 protects against steatohepatitis.
Wild-type mice (WT), Nrf2 gene-null mice (Nrf2-null) and Keap1 gene-knockdown mice (Keap1-kd), which represent the sustained activation of Nrf2, were fed a methionine- and choline-deficient diet (MCDD) for 13 weeks and analyzed.
In Keap1-kd fed an MCDD, steatohepatitis did not develop over the observation periods; however, in Nrf2-null fed an MCDD, the pathological state of the steatohepatitis was aggravated in terms of fatty change, inflammation, fibrosis and iron accumulation. In WT mice fed an MCDD, Nrf2 and antioxidative stress genes regulated by Nrf2 were potently activated in the livers, and in Keap1-kd, their basal levels were potently activated. Oxidative stress was significantly increased in the livers of the Nrf2-null and suppressed in the livers of the Keap1-kd compared to that of WT, based on the levels of 4-hydroxy-2-nonenal and malondialdehyde. Iron accumulation was greater in the livers of the Nrf2-null mice compared to those of the WT mice, and it was not observed in Keap1-kd. Further, the iron release from the isolated hepatocyte of Nrf2-null mice was significantly decreased. Sulforaphane, an activator of Nrf2, suppressed the pathological states and oxidative stress in the livers.
Nrf2 has protective roles against nutritional steatohepatitis through inhibition of hepatic iron accumulation and counteraction against oxidative stress-induced liver injury. Nrf2 activation by pharmaceutical intervention could be a new option for the prevention and treatment of steatohepatitis.
转录因子核因子 E2 相关因子 2（Nrf2）是诱导肝抗氧化应激系统的关键调节因子。我们旨在研究 Nrf2 的激活是否能预防脂肪性肝炎。
野生型小鼠（WT）、Nrf2 基因缺失小鼠（Nrf2-null）和 Keap1 基因敲低小鼠（Keap1-kd），它们代表 Nrf2 的持续激活，被喂食蛋氨酸和胆碱缺乏饮食（MCDD）13 周并进行分析。
在 Keap1-kd 喂食 MCDD 的情况下，在观察期间未发生脂肪性肝炎；然而，在 Nrf2-null 喂食 MCDD 的情况下，脂肪性肝炎的病理状态在脂肪变性、炎症、纤维化和铁积累方面加重。在 WT 喂食 MCDD 的情况下，Nrf2 和 Nrf2 调节的抗氧化应激基因在肝脏中被强烈激活，而在 Keap1-kd 中，它们的基础水平被强烈激活。与 WT 相比，Nrf2-null 和 Keap1-kd 的肝脏氧化应激显著增加，基于 4-羟基-2-壬烯醛和丙二醛的水平。与 WT 相比，Nrf2-null 小鼠肝脏中的铁积累更多，而在 Keap1-kd 中则没有观察到。此外，Nrf2-null 小鼠分离肝细胞的铁释放明显减少。Nrf2 的激活剂——萝卜硫素，抑制了肝脏的病理状态和氧化应激。
Nrf2 通过抑制肝铁积累和对抗氧化应激诱导的肝损伤，对营养性脂肪性肝炎具有保护作用。通过药物干预激活 Nrf2 可能是预防和治疗脂肪性肝炎的新选择。
