Xu Weihua, Hellerbrand Claus, Köhler Ulrike A, Bugnon Philippe, Kan Yuet-Wai, Werner Sabine, Beyer Tobias A
Department of Biology, Institute of Cell Biology, ETH Zürich, Switzerland.
Lab Invest. 2008 Oct;88(10):1068-78. doi: 10.1038/labinvest.2008.75. Epub 2008 Aug 4.
The liver is frequently exposed to insults, including toxic chemicals and alcohol, viral infection or metabolic overload. Although it can fully regenerate after acute injury, chronic liver damage causes liver fibrosis and cirrhosis, which can result in complete liver failure. In this study, we demonstrate that the NF-E2-related factor 2 (Nrf2) transcription factor protects the liver from acute and chronic toxin-mediated damage. Repair of the liver injury that occurs after a single treatment with the hepatotoxin carbon tetrachloride (CCl(4)) was severely delayed in Nrf2-deficient mice. The defect in repair was accompanied by an enhanced and prolonged inflammatory and profibrotic response. After long-term CCl(4) treatment, liver fibrosis was strongly aggravated in the Nrf2 knockout mice and inflammation was enhanced. We demonstrate that these abnormalities are at least in part due to the reduced expression of known and novel Nrf2 target genes in hepatocytes, which encode enzymes involved in the detoxification of CCl(4) and its metabolites. These results suggest that activation of Nrf2 may be a novel strategy to prevent or ameliorate toxin-induced liver injury and fibrosis.
肝脏经常受到各种损伤，包括接触有毒化学物质和酒精、病毒感染或代谢过载。尽管肝脏在急性损伤后能够完全再生，但慢性肝损伤会导致肝纤维化和肝硬化，进而可能导致肝衰竭。在本研究中，我们证明核因子E2相关因子2（Nrf2）转录因子可保护肝脏免受急性和慢性毒素介导的损伤。在用肝毒素四氯化碳（CCl4）单次处理后发生的肝损伤修复在Nrf2缺陷小鼠中严重延迟。修复缺陷伴随着炎症和促纤维化反应的增强和延长。长期CCl4处理后，Nrf2基因敲除小鼠的肝纤维化严重加剧，炎症增强。我们证明这些异常至少部分归因于肝细胞中已知和新的Nrf2靶基因表达降低，这些基因编码参与CCl4及其代谢产物解毒的酶。这些结果表明，激活Nrf2可能是预防或改善毒素诱导的肝损伤和纤维化的新策略。
