Overexpression of Nrf2 Protects against Microcystin-Induced Hepatotoxicity in Mice
dc.contributor.author | Lu, Yuan-Fu | |
dc.contributor.author | Liu, Jie Jerry | |
dc.contributor.author | Wu, Kai Connie | |
dc.contributor.author | Fan, Fang | |
dc.contributor.author | Klaassen, Curtis D. | |
dc.date.accessioned | 2014-04-28T17:28:18Z | |
dc.date.available | 2014-04-28T17:28:18Z | |
dc.date.issued | 2014-02-25 | |
dc.identifier.citation | Lu Y-F, Liu J, Wu KC, Qu Q, Fan F, et al. (2014) Overexpression of Nrf2 Protects against Microcystin-Induced Hepatotoxicity in Mice. PLoS ONE 9(3): e93013. http://dx.doi.org/10.1371/journal.pone.0093013 | |
dc.identifier.uri | http://hdl.handle.net/1808/13604 | |
dc.description.abstract | Oxidative stress and glutathione (GSH) depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO) mice were treated with microcystin (50 μg/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1β and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60–70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gstα1, Gstα4, Gstμ, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc). Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury. | |
dc.description.sponsorship | This work was supported by National Institutes of Health (NIH) grants DK-081461 and ES-019487, as well as by a Chinese National Science Foundation Grant 81160415. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | |
dc.publisher | Public Library of Science | |
dc.rights | ©2014 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Chemokines | |
dc.subject | Gene expression | |
dc.subject | Glutathione | |
dc.subject | Hepatocytes | |
dc.subject | Inflammation | |
dc.subject | Necrosis | |
dc.subject | Oxidative stress | |
dc.subject | Toxicity | |
dc.title | Overexpression of Nrf2 Protects against Microcystin-Induced Hepatotoxicity in Mice | |
dc.type | Article | |
kusw.kuauthor | Lu, Yuan-Fu | |
kusw.kuauthor | Liu, Jie Jerry | |
kusw.kuauthor | Wu, Kai Connie | |
kusw.kuauthor | Qu, Qiang | |
kusw.kuauthor | Klaassen, Curtis D. | |
kusw.kudepartment | Molecular Biosciences | |
kusw.oanotes | PUBMED CENTRAL project: This item has a Creative Commons license that allows it to be shared in KU ScholarWorks. | |
kusw.oastatus | fullparticipation | |
dc.identifier.doi | 10.1371/journal.pone.0093013 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: ©2014 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.