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 nrf1 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 homeostasis 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. hepatocellular carcinoma ͉ oxidative stress ͉ knockout mouse T ranscription of many cytoprotective genes and phase-2 xenobiotic metabolizing genes is regulated through cis-active sequences known as antioxidant response elements (ARE) (1, 2). Regulation of ARE function is mediated by various basic leucine zipper (bZIP) transcription factors including members of the ''cap n collar'' (CNC)-bZIP and small-Maf family of proteins. Nrf1 and Nrf2 are CNC-bZIP proteins, and they function as obligate heterodimers by complexing with small-Maf and other bZIP proteins (3). An important role for Nrf2 in xenobiotic metabolism and oxidative stress response had been identified through knockout studies in mice (4-10). These and other studies indicate that Nrf2 is an important activator of AREs.In contrast, the function of Nrf1 is not fully understood. Mice deficient in Nrf1 function die during development (11). Analysis of nrf1 and nrf1::nrf2 mutant cells suggests that Nrf1 is also involved in the oxidative stress response (12, 13). However, the importance of Nrf1 in this function in an intact animal is not certain because early lethality precludes analysis of Nrf1-deficient animals beyond embryonic development. Chimeric mice generated with Nrf1-deficient embryonic stem cells showed widespread apoptosis in fetal livers at late gestation, demonstrating a cell autonomous role of Nrf1 in the survival of hepatocytes (14). This finding suggests that Nrf1 is required for normal function of hepatocytes. Based on these findings, we hypothesize that Nrf1 is critical to the oxidative stress response in the adult liver, and that it plays an important role in oxidative stress-induced liver disease. To bypass embryonic lethality, we used a Cre-lox system ...

The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibited increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1 ؊/؊ fetal hepatocytes were sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF). Our results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development.

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We report a simple and facile solid-state approach to large-scale synthesis of multiwalled carbon nanotubes (MCNTs), for the first time, by one-step direct thermolysis of a metal-organic framework [Ni(3)(btc)(2).12H(2)O] (btc = benzene-1,3,5-tricarboxylato) in a one-end closed conventional horizontal tube furnace under relatively low temperature without using any additional carrier gas or catalyst.

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