Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes |
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Authors: | Tadayuki Tsujita Vivian Peirce Liam Baird Yuka Matsuyama Misaki Takaku Shawn V. Walsh Julian L. Griffin Akira Uruno Masayuki Yamamoto John D. Hayes |
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Affiliation: | aDivision of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom;bDepartment of Biochemistry, University of Cambridge, Cambridge, United Kingdom;cDepartment of Pathology, Ninewells Hospital, Tayside NHS Trust, Dundee, Scotland, United Kingdom;dDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan |
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Abstract: | Liver-specific Nrf1 (NF-E2-p45-related factor 1) knockout mice develop nonalcoholic steatohepatitis. To identify postnatal mechanisms responsible for this phenotype, we generated an inducible liver-specific Nrf1 knockout mouse line using animals harboring an Nrf1flox allele and a rat CYP1A1-Cre transgene (Nrf1flox/flox::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1flox/flox::CYP1A1-Cre+3MC mice) resulted in loss of hepatic Nrf1 expression. The livers of mice lacking Nrf1 accumulated lipid, and the hepatic fatty acid (FA) composition in such animals differed significantly from that in the Nrf1flox/flox::CYP1A1-Cre control. This change was provoked by upregulation of several FA metabolism genes. Unexpectedly, we also found that the level of glutathione was increased dramatically in livers of Nrf1flox/flox::CYP1A1-Cre+3MC mice. While expression of glutathione biosynthetic enzymes was unchanged, xCT, a component of the cystine/glutamate antiporter system xc−, was significantly upregulated in livers of Nrf1flox/flox::CYP1A1-Cre+3MC mice, suggesting that Nrf1 normally suppresses xCT. Thus, stress-inducible expression of xCT is a two-step process: under homeostatic conditions, Nrf1 effectively suppresses nonspecific transactivation of xCT, but when cells encounter severe oxidative/electrophilic stress, Nrf1 is displaced from an antioxidant response element (ARE) in the gene promoter while Nrf2 is recruited to the ARE. Thus, Nrf1 controls both the FA and the cystine/cysteine content of hepatocytes by participating in an elaborate regulatory network. |
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