Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury.
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.
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, the Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 200025.
Yan
Y
Guo
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275.
Bingfang
B
Hu
Department of Surgery, and.
Hai
H
Huang
Department of Surgery, and.
Allan
A
Tsung
the Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, and.
Nilesh W
NW
Gaikwad
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences.
Meishu
M
Xu
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences.
Mengxi
M
Jiang
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences.
Songrong
S
Ren
Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240.
Jie
J
Fan
Department of Surgery, and.
Timothy R
TR
Billiar
the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275.
Min
M
Huang
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, wex6@pitt.edu.
Wen
W
Xie
D000818:Animals; D002478:Cells, Cultured; D004967:Estrogens / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012737:Sex Factors; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D004967:Estrogens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015238:Sulfotransferases; C020122:estrone sulfotransferase
Nrf2; estrogen homeostasis; estrogen sulfotransferase; liver ischemia and reperfusion; oxidative stress