Abstract
The Keap1-Nrf2 system is an evolutionarily conserved defense mechanism against oxidative and xenobiotic stress. Besides the exogenous stress response, Nrf2 has been found to regulate numerous cellular functions, including protein turnover and glucose metabolism; however, the evolutionary origins of these functions remain unknown. In the present study, we searched for novel target genes associated with the zebrafish Nrf2 to answer this question. A microarray analysis of zebrafish embryos that overexpressed Nrf2 revealed that 115 candidate genes were targets of Nrf2, including genes encoding proteasome subunits and enzymes involved in glucose metabolism. A real-time quantitative PCR suggested that the expression of 3 proteasome subunits (psma3, psma5, and psmb7) and 2 enzymes involved in glucose metabolism (pgd and fbp1a) were regulated by zebrafish Nrf2. We thus next examined the upregulation of these genes by an Nrf2 activator, diethyl maleate, using Nrf2 mutant zebrafish larvae. The results of real-time quantitative PCR and whole-mount in situ hybridization showed that all of these 5 genes were upregulated by diethyl maleate treatment in an Nrf2-dependent manner, especially in the liver. These findings implied that the Nrf2-mediated regulation of the proteasome subunits and glucose metabolism is evolutionarily conserved among vertebrates.
Highlights
The Keap1-Nrf2 system is a mechanism that protects cells against xenobiotic and oxidative stress
The analysis revealed genes encoding proteasome subunits and enzymes involved in glucose metabolism, suggesting that the Nrf2-mediated regulation of both protein turnover and glucose metabolism is evolutionarily conserved among vertebrates
Weak DEMinduced expression of fbp1a was observed in the gills, but this induction was independent of nrf2a genotypes. These results indicate that the Keap1-Nrf2 system, at least in part, regulates the transcription of these enzymes involved in glucose metabolism
Summary
The Keap1-Nrf system is a mechanism that protects cells against xenobiotic and oxidative stress. Transcription factor Nrf transactivates a wide array of genes, which perform a range of functions, including (but not limited to) the encoding of antioxidant proteins, glutathioneconjugating enzymes, and xenobiotic transporters This confers an inducible defense against stressors [1, 2]. Nrf regulates the protein turnover by inducing proteasome subunits to confer protective effects against chronic diseases [4] and modifies cellular metabolic processes, for example, the pentose phosphate pathway, which provides NADPH and purine nucleotides that are essential for the redox homeostasis and cellular proliferation [5, 6]. Nrf research has become an emerging topic in the medical field [7, 8]
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