Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes
Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes
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DOI：
10.1128/mcb.00110-14
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发表时间：
2014-10-01
影响因子：
5.3
通讯作者：
Hayes, John D.
中科院分区：
文献类型：
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作者：
Tsujita, Tadayuki;Peirce, Vivian;Hayes, John D.
肝脏特异性Nrf 1（NF-E2-p45相关因子1）基因敲除小鼠发生非酒精性脂肪性肝炎为了确定这种表型的出生后机制，我们使用携带Nrf 1（flox）等位基因和大鼠CYP 1A 1-Cre转基因的动物（Nrf 1（flox）/（flox）：：CYP 1A 1-Cre小鼠）产生了可诱导的肝脏特异性Nrf 1敲除小鼠品系。对这些小鼠（Nrf 1（flox/flox）：：CYP 1A 1-Cre+3 MC小鼠）给予3-甲基胆蒽（3-MC）导致肝脏Nrf 1表达丧失。缺乏Nrf 1的小鼠肝脏脂质蓄积，这些动物的肝脏脂肪酸（FA）组成与Nrf 1（flox/flox）：：CYP 1A 1-Cre对照组显著不同。这种变化是由几个FA代谢基因的上调引起的。出乎意料的是，我们还发现Nrf 1（flox/flox）：：CYP 1A 1-Cre+3 MC小鼠肝脏中谷胱甘肽水平显著增加。虽然谷胱甘肽生物合成酶的表达没有变化，但胱氨酸/谷氨酸反向转运体系统xc-的一种组分xCT在Nrf 1（flox/flox）：：CYP 1A 1-Cre+3 MC小鼠的肝脏中显著上调，表明Nrf 1通常抑制xCT。因此，应激诱导的xCT表达是一个两步过程：在稳态条件下，Nrf 1有效抑制xCT的非特异性反式激活，但当细胞遇到严重的氧化/亲电应激时，Nrf 1从基因启动子中的抗氧化反应元件（ARE）中被取代，而Nrf 2被招募到ARE中。因此，Nrf 1通过参与一个复杂的调控网络来控制肝细胞的FA和胱氨酸/半胱氨酸含量。
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 Nrf1(flox) allele and a rat CYP1A1-Cre transgene (Nrf1(flox)/(flox)::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1(flox/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 Nrf1(flox/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 Nrf1(flox/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 Nrf1(flox/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.