Decrease in cholesterol in the cell membrane is essential for Nrf2 activation by quercetin
Decrease in cholesterol in the cell membrane is essential for Nrf2 activation by quercetin
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细胞膜中胆固醇的减少对于槲皮素激活 Nrf2 至关重要
DOI：
10.1016/j.jnutbio.2023.109329
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kawabe Tsutomu
中科院分区：
文献类型：
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作者：
Matsushima Miyoko;Nose Haruka;Tsuzuki Hikaru;Takekoshi Masahiro;Kusatsugu Yuto;Taniguchi Hinata;Ohdachi Tomoko;Hashimoto Naozumi;Sato Mitsuo;Kawabe Tsutomu
槲皮素是一种具有多种细胞保护作用的类黄酮。我们先前报道槲皮素通过诱导血红素加氧酶（HO）-1发挥抗过敏、抗氧化和抗纤维化活性。然而，槲皮素诱导HO-1表现出细胞保护作用的机制知之甚少。我们重点关注它对细胞膜的作用，细胞膜是细胞与细胞外环境相互作用的第一部分。细胞膜含有脂筏和小窝，在细胞信号转导中起重要作用。最近的研究表明，核因子E2相关因子2（Nrf 2），一种调节包括HO-1在内的抗氧化酶的转录因子，与小窝蛋白-1（Cav-1）相互作用，调节细胞的抗氧化能力。在这项研究中，我们调查了细胞膜的变化，导致诱导HO-1的槲皮素。槲皮素降低了筏组分中胆固醇的含量，这反过来又促进了HO-1的诱导。它还改变了脂筏的组成，减少和增加Cav-1的表达，筏和非筏部分，分别。Nrf 2在静息状态下定位于细胞膜，在接触槲皮素后沿着Cav-1移位至细胞核。这些发现首次表明槲皮素的HO-1依赖性细胞保护作用是通过减少细胞膜中胆固醇的量所引起的脂筏结构变化介导的，从而导致Cav-1-Nrf 2复合物易位到细胞核并诱导HO-1的表达。
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.