Estrogen receptor subcellular localization and cardiometabolism

Background: 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 (ER alpha), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ER alpha was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ER alpha AF-1 and ER alpha AF-2). However, besides these nuclear actions, a pool of ER alpha 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. Scope of the review: This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ER alpha 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 ER alpha effects recently allowed to begin to unravel the different modes of ER alpha signaling in vivo. Conclusion: Altogether, available data demonstrate the prominent role of ER alpha nuclear effects, and, more specifically, of ER alpha AF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ER alpha 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 ER alpha 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. (C) 2018 Published by Elsevier GmbH.