TY - JOUR
T1 - Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury
AU - Guo, Yan
AU - Hu, Bingfang
AU - Huang, Hai
AU - Tsung, Allan
AU - Gaikwad, Nilesh W.
AU - Xu, Meishu
AU - Jiang, Mengxi
AU - Ren, Songrong
AU - Fan, Jie
AU - Billiar, Timothy R.
AU - Huang, Min
AU - Xie, Wen
PY - 2015/6/5
Y1 - 2015/6/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930652236&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.642124
DO - 10.1074/jbc.M115.642124
M3 - Article
C2 - 25922074
AN - SCOPUS:84930652236
SN - 0021-9258
VL - 290
SP - 14754
EP - 14764
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 23
ER -