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.
Highlights
Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens
We showed that the ischemia and reperfusion (I/R)-responsive accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) protein was enhanced in female ESTϪ/Ϫ mice, likely because of compromised estrogen deprivation
We showed that the estrogen-deactivating enzyme EST was markedly induced in the mouse liver by I/R
Summary
Results: Liver ischemia and reperfusion (I/R) induced the expression of EST and comprised estrogen activity in an Nrf2-dependent manner. Oxidative stress-induced activation of Nrf was responsible for the EST induction, which was abolished in Nrf2؊/؊ mice. The effect of EST ablation was sex-specific because the EST؊/؊ males showed heightened I/R injury. Both estrogens and EST regulate the expression and activity of Nrf. The pathological events associated with I/R include direct hypoxic damage as the result of ischemia as well as a delayed and more severe oxidative damage that eventually leads to the activation of inflammatory pathways [2]. Stabilization and accumulation of HIF-1 or Nrf lead to the activation of an array of genes to adapt the cells to hypoxic or oxidative damages and, affect numerous cellular functions, such as cell apoptosis, proliferation, survival, metabolism, and angiogenesis [2, 4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
