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Pharmacogenomics of Chemically Distinct Classes of Keap1-Nrf2 Activators Identify Common and Unique Gene, Protein,
Ryan S Wible1, Quynh T Tran1, Samreen Fathima1
1Departments of Chemistry (R.S.W., T.R.S.) and Biological Sciences (C.H.S., T.R.S.,) and the W. Harry Feinstone Center for Genomic Research (R.S.W., S.F., T.R.S.), University of Memphis, Memphis, Tennessee; Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee (Q.T.T.); Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (T.W.K.); and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (T.W.K.).
Abstract:
The Kelch-like erythroid-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer and diabetes and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiologic outcomes. Here we used a robust chemical genomics approach to characterize expression profiles between D3T and CDDO-Im in livers from wild-type and Nrf2-null mice. At equally efficacious doses in wild-type mice, 406 genes show common RNA responses to both treatments. These genes enriched the Nrf2-regulated pathways of antioxidant defense and xenobiotic metabolism. In addition, 197 and 745 genes were regulated uniquely in response to either D3T or CDDO-Im, respectively. Functional analysis of the D3T-regulated set showed a significant enrichment of Nrf2-regulated enzymes involved in cholesterol biosynthesis. This result was supported by Nrf2-dependent increases in lanosterol synthase and CYP51 protein expression. CDDO-Im had no effect on cholesterol biosynthesis regardless of the dose tested. However, unlike D3T, CDDO-Im resulted in Nrf2-dependent elevation of peroxisome proliferator α and Kruppel-like factor 13, as well as the coactivator peroxisome proliferator γ coactivator 1β, together indicating regulation of β-oxidation and lipid metabolic pathways. These findings provide novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling. Although both compounds modify Keap1 to affect canonical cytoprotective gene expression, additional unique sets of Nrf2-dependent genes were regulated by each agent with enrichment of selective metabolic pathways.
Insights
Two distinct activators of the Keap1-Nrf2 pathway, D3T and CDDO-Im, show both shared and unique gene regulation. D3T uniquely impacts cholesterol biosynthesis, while CDDO-Im affects lipid metabolism pathways.
Area of Science:
- Molecular Biology
- Pharmacology
- Genomics
Background:
- The Kelch-like erythroid-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway is crucial for cellular defense and is targeted in various diseases.
- 3'H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are distinct chemical activators of the Nrf2 pathway.
- Previous studies suggest activator-specific effects of Nrf2 modulators on gene expression and physiological outcomes.
Purpose of the Study:
- To characterize and compare the gene expression profiles induced by D3T and CDDO-Im using a chemical genomics approach.
- To identify shared and unique Nrf2-dependent transcriptional responses to these two distinct Nrf2 activators.
- To elucidate the specific metabolic pathways regulated by each compound.
Main Methods:
- Utilized a chemical genomics strategy to analyze liver gene expression in wild-type and Nrf2-null mice treated with D3T and CDDO-Im.
- Quantified RNA expression changes to identify common and unique gene responses to both treatments at equally efficacious doses.
- Performed functional analysis on differentially regulated gene sets to determine enriched biological pathways.
Main Results:
- At equipotent doses, 406 genes showed common RNA responses to D3T and CDDO-Im, enriched in antioxidant defense and xenobiotic metabolism pathways.
- D3T uniquely regulated 197 genes, with significant enrichment in Nrf2-dependent cholesterol biosynthesis enzymes (e.g., lanosterol synthase, CYP51).
- CDDO-Im uniquely regulated 745 genes, indicating Nrf2-dependent regulation of beta-oxidation and lipid metabolism via peroxisome proliferator-activated receptors and coactivators.
Conclusions:
- D3T and CDDO-Im differentially modulate Nrf2-dependent gene expression beyond canonical cytoprotective pathways.
- D3T specifically activates Nrf2-dependent cholesterol biosynthesis, while CDDO-Im influences lipid metabolic pathways.
- These findings offer novel insights into the pharmacodynamic actions and selective metabolic effects of distinct Keap1-Nrf2 pathway activators.
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