Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.
Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.
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DOI：
10.1124/jpet.115.231316
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Dai, Guoli
中科院分区：
文献类型：
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作者：
Rui, Wenjuan;Zou, Yuhong;Dai, Guoli
转录因子核因子红系2相关因子2 （Nrf2）调节多种生物过程，包括肝脏脂质代谢。雌激素发挥影响能量稳态的作用，包括肝脏降脂作用。越来越多的证据表明这两个分子之间存在着串扰。本研究的目的是评估Nrf2是否调节肝脏脂质代谢中的雌激素信号。采用高脂饮食诱导野生型和nrf2缺失小鼠非酒精性脂肪性肝病（NAFLD），随后评估外源性雌激素对肝脏降脂的作用。我们发现，在野生型和nrf2缺失的NAFLD小鼠中，外源性雌激素分别消除了49%和90%的肝脏甘油三酯。这一观察结果表明Nrf2信号在肝脏脂肪代谢中与雌激素信号拮抗；因此，Nrf2缺失导致雌激素的肝脏降脂作用显著增强。此外，我们发现三叶因子3和脂肪酸结合蛋白5与雌激素的肝脏降脂作用有关。总之，我们发现Nrf2是一种新的有效的肝脂质代谢雌激素信号抑制剂。我们的发现可能提供一种通过双重靶向Nrf2和雌激素信号治疗NAFLD的潜在策略。
Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.