Liu Suhuan, Le May Cedric, Wong Winifred P S, Ward Robert D, Clegg Deborah J, Marcelli Marco, Korach Kenneth S, Mauvais-Jarvis Franck
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA.
Diabetes. 2009 Oct;58(10):2292-302. doi: 10.2337/db09-0257. Epub 2009 Jul 8.
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.
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.
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.
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.
我们已证明，在小鼠中，17β-雌二醇（E₂）通过雌激素受体α（ERα）促进胰腺β细胞存活。E₂ 通过雌激素反应元件（ERE）激活核雌激素受体。E₂ 还通过 ERα 的核外形式和 G 蛋白偶联雌激素受体（GPER）激活非基因组信号。我们研究了雌激素受体对胰岛存活的作用。
我们使用了缺乏雌激素受体α（αERKO⁻/⁻）、雌激素受体β（βERKO⁻/⁻）、雌激素受体α和雌激素受体β（αβERKO⁻/⁻）以及 GPER（GPERKO⁻/⁻）的小鼠和胰岛；一只缺乏与 ERE 结合的 ERα 的小鼠；以及人胰岛。这些小鼠和胰岛与受体特异性药理学探针联合进行研究。
我们表明，ERα 对胰岛存活的保护作用不依赖于 ERE，且 E₂ 通过核外和膜雌激素受体信号促进胰岛存活。我们表明，与 ERα 相比，ERβ 发挥的细胞保护作用较小。因此，βERKO⁻/⁻ 小鼠对链脲佐菌素诱导的胰岛凋亡有轻度易感性。然而，在小鼠中同时消除 ERα 和 ERβ 并不会协同引发胰岛凋亡。在 αβERKO⁻/⁻ 小鼠及其胰岛中，E₂ 部分预防凋亡，这表明一条替代途径可补偿 ERα/ERβ 缺陷。我们发现，一种膜不透性的 E₂ 制剂和一种选择性 GPER 激动剂可重现 E₂ 对胰岛存活的保护作用。因此，GPERKO⁻/⁻ 小鼠易患链脲佐菌素诱导的胰岛素缺乏症。
E₂ 通过 ERα 和 ERβ，经不依赖 ERE 的核外机制以及依赖 GPER 的机制保护β细胞存活。本研究为β细胞中的雌激素生物学增添了新的维度，并将 GPER 确定为保护胰岛存活的靶点。
