The Kelch-like erythroid-associated protein 1 (Keap1)ââ?¬â??NF-E2-\nrelated factor 2 (Nrf2) signaling pathway is the subject of several\nclinical trials evaluating the effects of Nrf2 activation on the\nprevention of cancer and diabetes and the treatment of chronic\nkidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione\n(D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-\nimidazole (CDDO-Im) are representative members of two distinct\nseries of Nrf2 chemical activators. Previous reports have described\nactivator-specific effects on Nrf2-dependent gene regulation\nand physiologic outcomes. Here we used a robust\nchemical genomics approach to characterize expression profiles\nbetween D3T and CDDO-Im in livers from wild-type and Nrf2-null\nmice. At equally efficacious doses in wild-type mice, 406 genes\nshow common RNA responses to both treatments. These genes\nenriched the Nrf2-regulated pathways of antioxidant defense\nand xenobiotic metabolism. In addition, 197 and 745 genes were\nrespectively. Functional analysis of the D3T-regulated set showed\na significant enrichment of Nrf2-regulated enzymes involved in\ncholesterol biosynthesis. This result was supported by Nrf2-\ndependent increases in lanosterol synthase and CYP51 protein\nexpression. CDDO-Im had no effect on cholesterol biosynthesis\nregardless of the dose tested. However, unlike D3T, CDDO-Im\nresulted in Nrf2-dependent elevation of peroxisome proliferator a\nand Kruppel-like factor 13, as well as the coactivator peroxisome\nproliferator Ãâ?? coactivator 1b, together indicating regulation of\nb-oxidation and lipid metabolic pathways. These findings provide\nnovel insights into the pharmacodynamic action of these two\nactivators of Keap1-Nrf2 signaling. Although both compounds\nmodify Keap1 to affect canonical cytoprotective gene expression,\nadditional unique sets of Nrf2-dependent genes were regulated by\neach agent with enrichment of selective metabolic pathways.
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