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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

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

Wenjuan Rui, Yuhong Zou, Joonyong Lee, Shashank Manohar Nambiar, Jingmei Lin, Linjie Zhang, Yan Yang and Guoli Dai
Journal of Pharmacology and Experimental Therapeutics July 2016, 358 (1) 14-21; DOI: https://doi.org/10.1124/jpet.115.231316
Wenjuan Rui
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Yuhong Zou
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Joonyong Lee
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Shashank Manohar Nambiar
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Jingmei Lin
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Linjie Zhang
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Yan Yang
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Guoli Dai
Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University–Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
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Abstract

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.

Footnotes

    • Received January 19, 2016.
    • Accepted May 5, 2016.
  • W.R. and Y.Z. contributed equally to this work.

  • This research was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 7R01DK07596].

  • dx.doi.org/10.1124/jpet.115.231316.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 1
1 Jul 2016
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Crosstalk of Nrf2 and Estrogen Signaling in Lipid Metabolism

Wenjuan Rui, Yuhong Zou, Joonyong Lee, Shashank Manohar Nambiar, Jingmei Lin, Linjie Zhang, Yan Yang and Guoli Dai
Journal of Pharmacology and Experimental Therapeutics July 1, 2016, 358 (1) 14-21; DOI: https://doi.org/10.1124/jpet.115.231316

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Crosstalk of Nrf2 and Estrogen Signaling in Lipid Metabolism

Wenjuan Rui, Yuhong Zou, Joonyong Lee, Shashank Manohar Nambiar, Jingmei Lin, Linjie Zhang, Yan Yang and Guoli Dai
Journal of Pharmacology and Experimental Therapeutics July 1, 2016, 358 (1) 14-21; DOI: https://doi.org/10.1124/jpet.115.231316
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