Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse, Toulouse, France; Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU de Toulouse, Toulouse, France.
Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse, Toulouse, France; Service d'Hépatologie et Gastro-Entérologie, CHU de Toulouse, Toulouse, France.
Mol Metab. 2018 Sep;15:56-69. doi: 10.1016/j.molmet.2018.05.009. Epub 2018 May 16.
In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells.
This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo.
Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of "old" ER modulators and to design new ones with an optimized benefit/risk profile.
雌激素除了在生殖方面发挥关键作用外，还是能量和葡萄糖稳态的重要调节剂，它们还具有多种心血管保护作用。这些有益作用主要通过雌激素受体 α（ERα）介导，ERα广泛表达于代谢和血管组织中。作为核受体超家族的一员，ERα最初被认为是一种转录因子，通过激活其两个激活功能区（ERαAF-1 和 ERαAF-2）来控制基因表达。然而，除了这些核作用外，还有一部分 ERα位于质膜附近，在那里它介导快速信号作用，称为膜起始甾体信号（MISS），这在体外，特别是在内皮细胞中已有很好的描述。
本综述旨在总结我们目前对核受体与膜受体 ERα 激活机制的认识，这些机制有助于雌激素发挥心脏代谢保护作用。事实上，新的转基因小鼠模型（影响 DNA 结合、激活功能或膜定位），以及最近使用选择性激活膜 ERα 作用的新型药理学工具，开始揭示了 ERα 在体内的不同信号转导模式。
总之，现有数据表明 ERα 核效应，特别是 ERαAF-2，在雌激素预防肥胖、糖尿病和动脉粥样硬化方面发挥着重要作用。然而，膜 ERα 信号选择性地介导了雌激素对内皮/血管的一些作用（NO 释放、再内皮化），也可能有助于调节能量平衡、胰岛素敏感性和葡萄糖代谢。这种对 ERα 生物学功能与其亚细胞定位相关的细分，将有助于理解“旧”ER 调节剂的作用机制，并设计具有优化的获益/风险比的新型调节剂。
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