Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice
ABSTRACT 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.
- SourceAvailable from: ncbi.nlm.nih.gov
[Show abstract] [Hide abstract]
- "Very recently, the role of Nrf2 was reported in mice fed the MCD diet for 2 weeks (Chowdhry et al., 2009), 3 weeks, and 6 weeks (Sugimoto et al., 2009). Consistent with the current study, the previous studies also show that the absence of Nrf2 resulted in a lack of activation of detoxification and antioxidation systems as well as increased oxidative stress and hepatoseatosis in the MCD model. "
ABSTRACT: Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstalpha1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.Toxicology and Applied Pharmacology 03/2010; 245(3):326-34. DOI:10.1016/j.taap.2010.03.016 · 3.63 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The Quaternary glacial landforms, such as cirques, glacial troughs, rockdrumlins and lateral moraines are discovered in the area of the middle-lower reaches of the Yangtze river. The isograms of gravels in the moraines reveal that the a-axes of the gravels are mostly parallel to the trends of the valleys. The inclinations of the a-axes of the gravels are 18°–23°. The tendency of the ab-pianes is varied. The inclinations of ab-planes are 15°–20°. The fine grains in the moraines are of bimodal form in the size-frequency curves. The surface of the quartz grains of the moraines possess typical characteristics of glacial sands. Based on the feature of glacial landforms and the data of analysis of the experiment in the laboratory, authors divide the climatic period of Quaternary in this area into four glacial stages.GeoJournal 03/1989; 18(2):221-222. DOI:10.1007/BF01207095