Bayele Henry K, Debnam Edward S, Srai Kaila S
Department of Structural & Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Department of Neuroscience, Physiology, and Pharmacology, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
Biochem Biophys Res Commun. 2016 Jan 15;469(3):521-8. doi: 10.1016/j.bbrc.2015.11.103. Epub 2015 Dec 2.
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.
肝脏表达一系列细胞保护基因，这些基因赋予细胞对氧化应激和外源性毒素的抗性，并预防癌症和其他与应激相关的疾病。这些基因主要受Nrf2调控，这使得该转录因子成为治疗此类疾病的小分子发现的靶点。在本报告中，我们鉴定出膳食多酚类抗氧化剂，它们不仅能激活这些基因，还能缓解Keap1对Nrf2的抑制作用。Keap1是一种依赖Cul3的泛素连接酶衔接蛋白，介导Nrf2的降解。与对照组相比，餐后肝脏RNA分析显示，所有测试多酚均能显著激活这两种基因。RNA干扰抑制Nrf2可降低多酚对其靶基因表达的影响。我们的数据表明，多酚可能通过解除Keap1对Nrf2的抑制来诱导细胞防御基因。我们推测，这种解除Nrf2抑制并重新激活其靶基因的能力可能是多酚对氧化应激相关疾病产生保护作用的基础。
