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Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival

OBJECTIVE: We showed that 17β-estradiol (E(2)) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupl...

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Autores principales: Liu, Suhuan, Le May, Cedric, Wong, Winifred P.S., Ward, Robert D., Clegg, Deborah J., Marcelli, Marco, Korach, Kenneth S., Mauvais-Jarvis, Franck
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750222/
https://www.ncbi.nlm.nih.gov/pubmed/19587358
http://dx.doi.org/10.2337/db09-0257
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author Liu, Suhuan
Le May, Cedric
Wong, Winifred P.S.
Ward, Robert D.
Clegg, Deborah J.
Marcelli, Marco
Korach, Kenneth S.
Mauvais-Jarvis, Franck
author_facet Liu, Suhuan
Le May, Cedric
Wong, Winifred P.S.
Ward, Robert D.
Clegg, Deborah J.
Marcelli, Marco
Korach, Kenneth S.
Mauvais-Jarvis, Franck
author_sort Liu, Suhuan
collection PubMed
description OBJECTIVE: We showed that 17β-estradiol (E(2)) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS: We used mice and islets deficient in estrogen receptor-α (αERKO(−/−)), estrogen receptor-β (βERKO(−/−)), estrogen receptor-α and estrogen receptor-β (αβERKO(−/−)), and GPER (GPERKO(−/−)); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS: We show that ERα protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO(−/−) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO(−/−) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(−/−) mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS: E(2) protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival.
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spelling pubmed-27502222010-10-01 Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival Liu, Suhuan Le May, Cedric Wong, Winifred P.S. Ward, Robert D. Clegg, Deborah J. Marcelli, Marco Korach, Kenneth S. Mauvais-Jarvis, Franck Diabetes Original Article OBJECTIVE: We showed that 17β-estradiol (E(2)) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS: We used mice and islets deficient in estrogen receptor-α (αERKO(−/−)), estrogen receptor-β (βERKO(−/−)), estrogen receptor-α and estrogen receptor-β (αβERKO(−/−)), and GPER (GPERKO(−/−)); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS: We show that ERα protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO(−/−) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO(−/−) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(−/−) mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS: E(2) protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival. American Diabetes Association 2009-10 2009-07-08 /pmc/articles/PMC2750222/ /pubmed/19587358 http://dx.doi.org/10.2337/db09-0257 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Article
Liu, Suhuan
Le May, Cedric
Wong, Winifred P.S.
Ward, Robert D.
Clegg, Deborah J.
Marcelli, Marco
Korach, Kenneth S.
Mauvais-Jarvis, Franck
Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title_full Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title_fullStr Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title_full_unstemmed Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title_short Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival
title_sort importance of extranuclear estrogen receptor-α and membrane g protein–coupled estrogen receptor in pancreatic islet survival
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750222/
https://www.ncbi.nlm.nih.gov/pubmed/19587358
http://dx.doi.org/10.2337/db09-0257
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