Department of Gastroenterology,Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.
Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G283-94. doi: 10.1152/ajpgi.00296.2009. Epub 2009 Nov 19.
Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline-deficient (MCD) diet for 3 and 6 wk, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared with that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf2-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.
氧化应激是脂肪性肝炎肝损伤的关键介质。转录因子 Nrf2 作为细胞应激传感器，是诱导肝解毒和抗氧化应激系统的关键调节因子。Nrf2 参与抵抗脂肪性肝炎的发展尚不清楚。我们旨在使用野生型 (WT) 和 Nrf2 基因缺失 (Nrf2-null) 小鼠研究 Nrf2 在营养性脂肪性肝炎中的保护作用。WT 和 Nrf2-null 小鼠分别用蛋氨酸和胆碱缺乏 (MCD) 饮食喂养 3 周和 6 周，分析肝组织病理学和通过 Nrf2 转录途径表达解毒酶和抗氧化应激基因的水平。在 MCD 饮食喂养的 WT 小鼠中，Nrf2 在肝脏中被强烈激活，并且在观察期间没有发生脂肪性肝炎。然而，在 MCD 饮食喂养的 Nrf2-null 小鼠中，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。与 WT 小鼠相比，Nrf2-null 小鼠肝脏中的氧化应激显著增加，这是基于 4-羟基-2-壬烯醛和丙二醛水平的增加。这种变化与谷胱甘肽、解毒酶、过氧化氢酶和超氧化物歧化酶活性的降低有关。与肝病理变化密切相关的是，Nrf2-null 小鼠肝脏中与脂肪酸代谢、炎症细胞因子和纤维化相关基因相关的因子的 mRNA 水平显著增加。这些发现表明，MCD 饮食诱导的营养性脂肪性肝炎在小鼠中 Nrf2 缺失导致快速发作和进展。Nrf2 的激活可能是开发脂肪性肝炎预防和治疗新方法的有希望的靶点。
