title: The role of nuclear factor E2-Related factor 2 and uncoupling protein 2 in glutathione metabolism: Evidence from an in vivo gene knockout study.
abstract: Nuclear factor E2-related factor 2 (NRF2) and uncoupling protein 2 (UCP2) are indicated to protect from oxidative stress. They also play roles in the homeostasis of glutathione. However, the detailed mechanisms are not well understood. In the present study, we found Nrf2-knockout (Nrf2-KO) mice exhibited altered glutathione homeostasis and reduced expression of various genes involved in GSH biosynthesis, regeneration, utilization and transport in the liver. Ucp2-knockout (Ucp2-KO) mice exhibited altered glutathione homeostasis in the liver, spleen and blood, as well as increased transcript of cystic fibrosis transmembrane conductance regulator in the liver, a protein capable of mediating glutathione efflux. Nrf2-Ucp2-double knockout (DKO) mice showed characteristics of both Nrf2-KO and Ucp2-KO mice. But no significant difference was observed in DKO mice when compared with Nrf2-KO or Ucp2-KO mice, except in blood glutathione levels. These data suggest that ablation of Nrf2 and Ucp2 leads to disrupted GSH balance, which could result from altered expression of genes involved in GSH metabolism. DKO may not evoke more severe oxidative stress than the single gene knockout.
authors.affiliation: The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China; The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, PR China. Electronic address: yyxu@cmu.edu.cn.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China; The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, PR China; The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA. Electronic address: jbpi@cmu.edu.cn.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005978:Glutathione / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071246:Uncoupling Protein 2; D005978:Glutathione
keywords: Glutathione; Nuclear factor-erythroid 2-related factor 2; Oxidative stress; Uncoupling protein 2