title: Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.
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.
authors.affiliation: 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.).
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Rui
authors.affiliation: 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.).
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: 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.).
authors.forename: Joonyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: 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.).
authors.forename: Shashank Manohar
authors.initials: SM
authors.lastname: Nambiar
authors.affiliation: 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.).
authors.forename: Jingmei
authors.initials: J
authors.lastname: Lin
authors.affiliation: 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.).
authors.forename: Linjie
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.) gdai@iupui.edu yangyan@ahmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.) gdai@iupui.edu yangyan@ahmu.edu.cn.
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D047628:Estrogen Receptor alpha; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D051267:NF-E2-Related Factor 2; D009363:Neoplasm Proteins; C495636:Nfe2l2 protein, mouse; D004958:Estradiol