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首页> 外文期刊>Molecular and Cellular Biology >Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes
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Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes

机译：转录因子Nrf1负调节胱氨酸/谷氨酸转运蛋白和脂质代谢酶。

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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.
机译：肝脏特异性Nrf1（NF-E2-p45相关因子1）基因敲除小鼠发展为非酒精性脂肪性肝炎。为了确定造成该表型的产后机制，我们使用具有 Nrf1 flox 等位基因和一个等位基因的动物，生成了诱导型肝特异性Nrf1基因敲除小鼠品系大鼠 CYP1A1-Cre 转基因（ Nrf1 flox / flox :: CYP1A1-Cre 老鼠）。对这些小鼠（ Nrf1 flox / flox :: CYP1A1-Cre 的3-甲基胆碱（3-MC）给药> + 3MC小鼠）导致肝Nrf1表达丧失。缺乏Nrf1的小鼠肝脏中积累的脂质，这些动物中的肝脏脂肪酸（FA）组成与 Nrf1 flox / flox :: CYP1A1-Cre 控件。几种FA代谢基因的上调引起了这种变化。出乎意料的是，我们还发现 Nrf1 flox / flox :: CYP1A1-Cre <>肝脏中的谷胱甘肽水平急剧增加。 / em> + 3MC小鼠。虽然谷胱甘肽生物合成酶的表达没有变化，但是 Nrf1 中的胱氨酸/谷氨酸逆转运系统x c ？的组成部分xCT却显着上调。 em> flox / flox :: CYP1A1-Cre + 3MC小鼠，提示Nrf1正常抑制 xCT 。因此， xCT 的应激诱导表达过程分为两个步骤：在稳态条件下，Nrf1有效抑制 xCT 的非特异性反式激活，但是当细胞遇到严重的氧化/亲电应激时，Nrf1从基因启动子中的抗氧化剂反应元件（ARE）移出，而Nrf2被募集到ARE中。因此，Nrf1通过参与精细的调节网络来控制FA和肝细胞的半胱氨酸/半胱氨酸含量。

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