Format

Send to

Choose Destination
J Biol Chem. 2015 Jun 5;290(23):14754-64. doi: 10.1074/jbc.M115.642124. Epub 2015 Apr 28.

Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury.

Author information

1
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.
2
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275.
3
Department of Surgery, and.
4
the Department of Nutrition and Department of Environmental Toxicology, University of California, Davis, California 95616, and.
5
From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences.
6
Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240.
7
the Institute of Clinical Pharmacology, Sun Yat-Sen University, Guangzhou, China 510275.
8
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.

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.

KEYWORDS:

Nrf2; estrogen homeostasis; estrogen sulfotransferase; liver ischemia and reperfusion; oxidative stress

PMID:
25922074
PMCID:
PMC4505540
DOI:
10.1074/jbc.M115.642124
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center