Division of Host Defense Sciences, Omics Health Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Tokai National Higher Education and Research System, Nagoya, Japan.
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Tokai National Higher Education and Research System, Nagoya, Japan.
J Nutr Biochem. 2023 Jun;116:109329. doi: 10.1016/j.jnutbio.2023.109329. Epub 2023 Mar 22.
Quercetin is a flavonoid with various cytoprotective effects. We previously reported that quercetin exerts anti-allergic, anti-oxidative, and anti-fibrotic activities via the induction of heme oxygenase (HO)-1. However, the mechanisms by which quercetin induces HO-1 to exhibit cytoprotective effects are poorly understood. We focused on its action on the cell membrane, which is the first part of the cell to interact with the extracellular environment. The cell membrane contains lipid rafts and caveolae, which play important roles in cellular signaling. A recent study showed that nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating anti-oxidative enzymes including HO-1, interacts with caveolin-1 (Cav-1), a component of caveolae, to regulate cellular anti-oxidative capacity. In this study, we investigated the changes in the cell membrane that leads to the induction of HO-1 by quercetin. Quercetin decreased the amount of cholesterol in the raft fractions, which in turn promoted the induction of HO-1. It also changed the composition of the lipid rafts and decreased and increased the expression of Cav-1 in the raft and non-raft fractions, respectively. Nrf2, which was localized in the cell membrane under resting conditions, was translocated along with Cav-1 to the nucleus after exposure to quercetin. These findings indicate for the first time that the HO-1-dependent cytoprotective effects of quercetin are mediated by the structural changes in lipid rafts brought about by decreasing the amount of cholesterol in the cell membrane, which thereby results in the translocation of the Cav-1-Nrf2 complex to the nucleus and induces the expression of HO-1.
槲皮素是一种具有多种细胞保护作用的类黄酮。我们之前的研究表明，槲皮素通过诱导血红素加氧酶（HO）-1 发挥抗过敏、抗氧化和抗纤维化作用。然而，槲皮素诱导 HO-1 发挥细胞保护作用的机制尚不清楚。我们专注于其对细胞膜的作用，细胞膜是与细胞外环境首先相互作用的细胞的一部分。细胞膜含有脂质筏和 caveolae，它们在细胞信号转导中发挥重要作用。最近的一项研究表明，核因子 E2 相关因子 2（Nrf2），一种调节包括 HO-1 在内的抗氧化酶的转录因子，与 caveolin-1（Cav-1）相互作用，Cav-1 是 caveolae 的一个组成部分，调节细胞的抗氧化能力。在这项研究中，我们研究了导致槲皮素诱导 HO-1 的细胞膜变化。槲皮素减少了筏分馏物中的胆固醇含量，从而促进了 HO-1 的诱导。它还改变了脂质筏的组成，并分别降低和增加了筏和非筏分馏物中 Cav-1 的表达。在静息状态下位于细胞膜上的 Nrf2 在暴露于槲皮素后与 Cav-1 一起向核内易位。这些发现首次表明，槲皮素依赖 HO-1 的细胞保护作用是通过减少细胞膜中胆固醇的量引起的脂质筏的结构变化介导的，这导致 Cav-1-Nrf2 复合物向核内易位并诱导 HO-1 的表达。
