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

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

doi:10.1074/jbc.m115.642124

Cited by 44 publications

(39 citation statements)

References 36 publications

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“…Xie et al revealed a feedback mechanism between Nrf2 and estrogen in liver ischemia and reperfusion (I/R) Guo et al, 2015. I/R-induced Nrf2 activation directly upregulates estrogen sulfotransferase and in turn increases estrogen breakdown, limiting Nrf2 activity and gender-dependently affecting I/R injury (Guo et al, 2015). In addition, the crosstalk of Nrf2 signaling with the PTEN-GSK-3-b-TrCP pathway and the p62-mediated autophagy pathway has been demonstrated (Komatsu et al, 2010;Ni et al, 2014;Rojo et al, 2014;Taguchi et al, 2014).…”

Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismmentioning

confidence: 99%

Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismmentioning

confidence: 99%

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Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Wei

Zou

Lee

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.

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Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismmentioning

confidence: 99%

Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismmentioning

confidence: 99%

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Wei

Zou

Lee

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…The establishment of the hypoxia-reoxygenation (H/R) model in vitro was performed as previous described [21]. Briefly , the primary hepatocytes were placed into serum-free DMEM medium and seeded at a density of 4×10 5 cells/well in 6-well plates, which equilibrated with 1% O 2 , 5% CO 2 , and 94% N 2.…”

Section: Methodsmentioning

confidence: 99%

Protective Effects the Akt Activator SC79 in Hepatic Ischemia-Reperfusion Injury

Zhou

Zhang

et al. 2018

Med Sci Monit

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BackgroundSC79 has been reported to protect against experimental ischemia-elicited neuronal death and brain injury and to protect myocardiocytes from hypoxia/reoxygenation (H/R) injury. Here, we investigated the effects of SC79 in primary hepatocytes in vitro and in rat liver in vivo following hypoxia-reoxygenation (H/R) and hepatic I/R injury.Material/MethodsThe livers of Sprague-Dawley rats were subjected to 45 min of ischemia followed by 2–24 h of reperfusion. The primary hepatocytes were subjected to hypoxia for 6 h and for 2–24 h. The hepatocytes cells or the hepatic I/R injury model livers were treated with SC79 or/and LY294002 at different times and concentrations. The serum ALT, AST, histologic examination, cellular viability, and cell apoptosis were assessed. The levels of phospho-Akt, Bad, Bim, Bax, Bcl-2, and Bcl-XL were determined by Western blot analysis.ResultsSC79 improved viability and inhibited apoptosis in hepatocytes following H/R. SC79 decreased serum AST and ALT, markedly improved pathology, and decreased cell apoptosis in livers following I/R. In addition, SC79 promoted the expression of phospho-Akt, Bcl-2, and Bcl-XL, and decreased the expression of Bid, Bax, and Bim. PI3K inhibitor (LY294002) pre-treatment completely abolished the above-mentioned effects of SC79.ConclusionsThe protective role of SC79 against H/R of hepatocytes or hepatic I/R injury is related to activation of phosphorylation of Akt, resulting in the decrease of pro-apoptotic protein of Bim, Bax, and Bad, and increase of the anti-apoptotic protein Bcl-2 and Bcl-xL induced by cell H/R and hepatic I/R injury.

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“…We showed that the expression of EST was markedly induced by I/R in both male and female mice in a time-dependent manner. [36] Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for EST induction, which was abolished in the Nrf2-/- mice. We identified two Nrf2 binding sites, the antioxidant response element (ARE), in the mouse EST gene promoter and established EST as a direct transcriptional target of Nrf2.…”

Section: Regulation Of Hepatic Drug Metabolism By Liver I/rmentioning

confidence: 99%

“…Based on these results, we proposed that inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. [36]…”

Section: Regulation Of Hepatic Drug Metabolism By Liver I/rmentioning

confidence: 99%

Regulation of drug-metabolizing enzymes by local and systemic liver injuries

Guo

Xie

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Drug metabolism and disposition are critical in maintaining the chemical and functional homeostasis of xenobiotics/drugs and endobiotics. The liver plays an essential role in drug metabolism and disposition due to its abundant expression of drug-metabolizing enzymes (DMEs) and transporters. There is growing evidence to suggest that many hepatic and systemic diseases can affect drug metabolism and disposition by regulating the expression and/or activity of DMEs and transporters in the liver. Areas covered This review focuses on the recent progress on the regulation of DMEs by local and systemic liver injuries. Liver ischemia and reperfusion (I/R) and sepsis are used as examples of local and systemic injury, respectively. The reciprocal effect of the expression and activity of DMEs on animals' sensitivity to local and systemic liver injuries is also discussed. Expert opinion Local and systemic liver injuries have a major effect on the expression and activity of DMEs in the liver. Understanding the disease effect on DMEs is clinically important due to the concern of disease-drug interactions. Future studies are necessary to understand the mechanism by which liver injury regulates DMEs. Human studies are also urgently needed in order to determine whether the results in animals can be replicated in human patients.

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

Cited by 44 publications

References 36 publications

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Protective Effects the Akt Activator SC79 in Hepatic Ischemia-Reperfusion Injury

Regulation of drug-metabolizing enzymes by local and systemic liver injuries

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