Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury

Yan Guo, Bingfang Hu, Hai Huang, Allan Tsung, Nilesh W. Gaikwad, Meishu Xu, Mengxi Jiang, Songrong Ren, Jie Fan, Timothy R. Billiar, Min Huang, Wen Xie

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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<sup>-/-</sup> 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<sup>-/-</sup> 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<sup>-/-</sup> 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.

Original languageEnglish (US)
Pages (from-to)14754-14764
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number23
DOIs
StatePublished - Jun 5 2015

Fingerprint

Oxidative stress
Reperfusion Injury
Liver
Oxidative Stress
Genes
Estrogens
Reperfusion
Ischemia
Ovariectomy
Ablation
estrone sulfotransferase
Chemical activation
Homeostasis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury. / Guo, Yan; Hu, Bingfang; Huang, Hai; Tsung, Allan; Gaikwad, Nilesh W.; Xu, Meishu; Jiang, Mengxi; Ren, Songrong; Fan, Jie; Billiar, Timothy R.; Huang, Min; Xie, Wen.

In: Journal of Biological Chemistry, Vol. 290, No. 23, 05.06.2015, p. 14754-14764.

Research output: Contribution to journalArticle

Guo, Y, Hu, B, Huang, H, Tsung, A, Gaikwad, NW, Xu, M, Jiang, M, Ren, S, Fan, J, Billiar, TR, Huang, M & Xie, W 2015, 'Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury', Journal of Biological Chemistry, vol. 290, no. 23, pp. 14754-14764. https://doi.org/10.1074/jbc.M115.642124
Guo, Yan ; Hu, Bingfang ; Huang, Hai ; Tsung, Allan ; Gaikwad, Nilesh W. ; Xu, Meishu ; Jiang, Mengxi ; Ren, Songrong ; Fan, Jie ; Billiar, Timothy R. ; Huang, Min ; Xie, Wen. / Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 23. pp. 14754-14764.
@article{daf2f4244f454fe2b51bf84d6d460375,
title = "Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury",
abstract = "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.",
author = "Yan Guo and Bingfang Hu and Hai Huang and Allan Tsung and Gaikwad, {Nilesh W.} and Meishu Xu and Mengxi Jiang and Songrong Ren and Jie Fan and Billiar, {Timothy R.} and Min Huang and Wen Xie",
year = "2015",
month = "6",
day = "5",
doi = "10.1074/jbc.M115.642124",
language = "English (US)",
volume = "290",
pages = "14754--14764",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "23",

}

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

UR - http://www.scopus.com/inward/citedby.url?scp=84930652236&partnerID=8YFLogxK

U2 - 10.1074/jbc.M115.642124

DO - 10.1074/jbc.M115.642124

M3 - Article

C2 - 25922074

AN - SCOPUS:84930652236

VL - 290

SP - 14754

EP - 14764

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 23

ER -