title: Nrf2 transcriptional derepression from Keap1 by dietary polyphenols.
abstract: The liver expresses batteries of cytoprotective genes that confer cellular resistance to oxidative stress and xenobiotic toxins, and protection against cancer and other stress-related diseases. These genes are mainly regulated by Nrf2, making this transcription factor a target for small molecule discovery to treat such diseases. In this report, we identified dietary polyphenolic antioxidants that not only activated these genes but also relieved Nrf2 repression by Keap1, a Cul3-dependent ubiquitin ligase adaptor protein that mediates its degradation. Analysis of postprandial liver RNA revealed a marked activation of both genes by all test polyphenols compared with controls. Nrf2 inhibition by RNA interference reduced polyphenol effects on its target gene expression. Our data suggest that polyphenols may induce cellular defense genes by derepressing Nrf2 inhibition by Keap1. We posit that this ability to derepress Nrf2 and reactivate its target genes may underlie the protection conferred by polyphenols against oxidative stress-related diseases.
authors.affiliation: Department of Structural & Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, United Kingdom. Electronic address: h.bayele@ucl.ac.uk.
authors.forename: Henry K
authors.initials: HK
authors.lastname: Bayele
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Debnam
authors.affiliation: Department of Structural & Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Kaila S
authors.initials: KS
authors.lastname: Srai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019587:Dietary Supplements; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D059808:Polyphenols / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D059808:Polyphenols; D012097:Repressor Proteins
keywords: Antioxidant; Antioxidant response element; Cytoprotection; Detoxification; Dietary polyphenols