Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury
Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury
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雌激素磺基转移酶是一种氧化应激反应基因，对肝脏缺血/再灌注损伤具有性别特异性影响。
DOI：
10.1074/jbc.m115.642124
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发表时间：
2015-06-05
影响因子：
4.8
通讯作者：
Xie, Wen
中科院分区：
文献类型：
--
作者：
Guo, Yan;Hu, Bingfang;Xie, Wen
雌激素磺基转移酶（EST）通过磺基化和灭活雌激素来调节雌激素稳态。肝脏缺血再灌注（I/R）涉及缺血期的缺氧和再灌注期的氧化损伤。在本研究中，我们发现I/R显著诱导EST的表达。从机制上讲，氧化应激诱导的Nrf 2激活负责EST诱导，这在Nrf 2（-/-）小鼠中被取消。EST是Nrf 2的直接转录靶点。在雌性小鼠中，EST的I/R反应诱导损害了雌激素活性。由于雌激素剥夺减少，EST消融减弱了I/R损伤，而这种益处在卵巢切除术后被消除。EST消融的效果是性别特异性的，因为EST-/-男性显示出较高的I/R损伤。反过来，雌激素和EST调节Nrf 2的表达和活性。卵巢切除术雌激素剥夺废除了I/R反应性Nrf 2积累，而EST-/-小鼠中雌激素剥夺与Nrf 2积累增加相关。我们的研究结果提出了一种新的I/R响应反馈机制，以限制Nrf 2的活性，其中Nrf 2诱导EST的表达，随后增加雌激素失活并限制Nrf 2的雌激素响应激活。抑制EST，至少在女性中，可能是一种有效的方法来管理肝I/R损伤。
Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST-/- males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST-/- mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury.