Estrogen receptor subcellular localization and cardiometabolism

Abstract

BackgroundIn 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.Scope of the reviewThis 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.ConclusionAltogether, 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.

Selective Targeting of Non-nuclear Estrogen Receptors with PaPE-1 as a New Treatment Strategy for Alzheimer’s Disease

“…This property positions PaPE-1 as a unique pharmacological tool that possesses the neuroprotective potential of estrogen with limited uterotrophic effects and cancer risks. Recently, PaPE-1 was shown to decrease stroke severity in a mouse model of tMCAO (Selvaraj et al 2018 ), in addition to exerting cardiometabolic benefits (Gourdy et al 2018 ). Therefore, our present study widens the window of pharmacological utility of PaPE-1 for the treatment of AD.…”

Sex differences in metabolic regulation and diabetes susceptibility

“…Beyond lifestyle adaptations, hormone replacement therapy has been associated with reduced type 2 diabetes incidence in clinical trials, as previously mentioned [14,15], but the uncertainties regarding its benefit-risk balance do not allow for its extended use in this context. Menopausal women could, thus, particularly benefit from new selective oestrogen receptor modulators that are able to mediate the protective actions of oestrogens on body composition and glucose metabolism with limited side effects on reproductive tissues [63]. Tissue-specific targeting could also be a relevant strategy, as illustrated by the protection conferred by a GLP-1-oestrogen conjugate against dietinduced obesity and glucose intolerance in mice via selective ERα activation in the CNS and the pancreas [64].…”

Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells

“…Furthermore, Sirt3 silencing caused downregulation of ERα expression ( Figure 1D), indicating the involvement of Sirt3 in the ERα expression level. Since Sirt3 is a mitochondrial protein and ERα is mostly localized in the nucleus [37,38], it is unlikely that they interact. Some earlier studies proposed the regulation of a small fraction of ERα by estrogen in mitochondria (reviewed by [39]), but these claims are still controversial.…”