Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival.
OBJECTIVE
We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) 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 ERalpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival.


METHODS
We used mice and islets deficient in estrogen receptor-alpha (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.


RESULTS
We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta 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 beta-cell survival through ERalpha and ERbeta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival.
Liu
Suhuan
S
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA.
Le May
Cedric
C
Wong
Winifred P S
WP
Ward
Robert D
RD
Clegg
Deborah J
DJ
Marcelli
Marco
M
Korach
Kenneth S
KS
Mauvais-Jarvis
Franck
F
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000235:genetics; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000737:chemistry / Q000166:cytology; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013311:Streptozocin / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D007328:Insulin; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D013311:Streptozocin