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

29 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Estrogen sulfotransferase is an oxidative stress-responsive gene that gender-specifically affects liver ischemia/reperfusion injury'. Together they form a unique fingerprint.

  • Cite this

    Guo, Y., Hu, B., Huang, H., Tsung, A., Gaikwad, N. W., Xu, M., Jiang, M., Ren, S., Fan, J., Billiar, T. R., 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, 290(23), 14754-14764. https://doi.org/10.1074/jbc.M115.642124