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Activation of Nrf2 in the Liver is Associated with Suppression of the Growth Hormone-Regulated STAT5b Transcription Factor
Citation:
Rooney, J., K. Oshida, N. Vasani, B. Vallanat, N. Ryan, B. Chorley, X. Wang, D. Bell, K. Wu, L. Aleksunes, C. Klaassen, T. Kensler, AND C. Corton. Activation of Nrf2 in the Liver is Associated with Suppression of the Growth Hormone-Regulated STAT5b Transcription Factor. PLOS ONE . Public Library of Science, San Francisco, CA, 13(8):1-30, (2018). https://doi.org/10.1371/journal.pone.0200004
Impact/Purpose:
The transcription factor Nrf2 (encoded by Nfe2l2) induces expression of numerous detoxifying and antioxidant genes in response to oxidative stress. The cytoplasmic protein Keap1 interacts with and represses Nrf2 function. Computational approaches were developed to identify factors that modulate Nrf2 in a mouse liver gene expression compendium. A gene expression biomarker was used to identify factors in a microarray database that led to Nrf2 activation or suppression and were then correlated with STAT5b activation levels in both male and female mouse models.
Description:
The transcription factor Nrf2 (encoded by Nfe2l2) induces expression of numerous detoxifying and antioxidant genes in response to oxidative stress. The cytoplasmic protein Keap1 interacts with and represses Nrf2 function. Computational approaches were developed to identify factors that modulate Nrf2 in a mouse liver gene expression compendium. Forty-eight Nrf2 signature genes were identified using profiles from the livers of mice in which Nrf2 was activated genetically in Keap1-null mice or chemically by a potent activator of Nrf2 signaling. The rank-based Running Fisher statistical test was used to determine the correlation between the Nrf2 signature genes and a test set of 81 biosets with known Nrf2 activation status demonstrating a balanced accuracy of 96%. For a large number of factors examined in the compendium, we found consistent relationships between activation of Nrf2 and feminization of the liver transcriptome through suppression of the male-specific growth hormone (GH)-regulated transcription factor STAT5b. The livers of female mice exhibited higher Nrf2 activation than male mice in untreated or chemical-treated conditions. In male mice, Nrf2 was activated by treatment with ethinyl estradiol, whereas in female mice, Nrf2 was suppressed by treatment with testosterone. Nrf2 was activated in 5 models of disrupted GH signaling containing mutations in Pit1, Prop1, Ghrh, Ghrhr, and Ghr. Out of 59 chemical treatments that activated Nrf2, 36 exhibited STAT5b suppression in the male liver. The Nrf2-STAT5b coupling was absent in in vitro comparisons of chemical treatments. Treatment of male and female mice with 11 chemicals that induce oxidative stress showed that all chemicals activated Nrf2 to greater extents in females. The enhanced basal and inducible levels of Nrf2 activation in females relative to males provides a molecular explanation for the greater resistance often seen in females vs. males to age-dependent diseases and chemical-induced toxicity.
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DOI: Activation of Nrf2 in the Liver is Associated with Suppression of the Growth Hormone-Regulated STAT5b Transcription Factor