Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ERα signaling in type 2 diabetes mellitus (T2DM)
Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ERα signaling in type 2 diabetes mellitus (T2DM)
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Foxa3 通过转录调节 2 型糖尿病 (T2DM) 中 ERalpha 信号传导来调节睾丸类固醇生成。
DOI：
10.1016/j.bbrc.2017.06.118
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发表时间：
2017-08-26
影响因子：
3.1
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Zhao, Yong;Li, Hong-xin;Li, Wei
尽管已知胰岛素和雌激素受体α（ER α）都对睾丸类固醇生成产生抑制作用，但仍不清楚这些途径是否在某些病理条件下调节睾酮（T）的产生[例如，2型糖尿病（T2 DM）]。在这里，我们发现，叉头框蛋白A3（Foxa 3），一个重要的转录调节因子参与脂肪形成和能量代谢，在T缺陷型T2 DM小鼠的Leydig细胞（LC）的表达显着下调。在功能上，在hCG刺激后，Foxa 3募集到Esr 1启动子并抑制Esr 1基因的反式激活。T2 DM引起的高胰岛素血症对这种募集的破坏导致ER α途径的异常激活，抑制类固醇生成酶基因表达，从而导致T产生不足。在治疗上，胰岛素受损和Foxa 3消融受损的类固醇生成被ER α通路的药理学抑制剂有效地挽救。这些发现揭示了Foxa 3在调节ER α表达和Foxa 3/ER α级联中的强制性共调节作用，至少部分地在T2 DM引起的雄激素缺乏症的发病机制中。(C)2017爱思唯尔公司All rights reserved.
Although both insulin and estrogen receptor alpha (ER alpha) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged in adipogenesis and energy metabolism, was significantly down-regulated in the Leydig cells (LCs) from T-deficient T2DM mice. Functionally, upon hCG stimulation, Foxa3 recruits to the Esr1 promoter and suppresses the transactivation of Esr1 gene. Disruption of this recruitment by T2DM-elicited hyperinsulinemia led to abnormal activation of ER alpha pathway, inhibited steroidogenic enzyme genes expression, and thus caused inadequate T production. Therapeutically, insulin-impaired and Foxa3 ablation-compromised steroidogenesis were effectively rescued by a pharmacological inhibitor of the ER alpha pathway. These findings reveal an obligatory coregulatory role of Foxa3 in the regulation of ER alpha expression and of the Foxa3/ER alpha cascade, at least in part, in the pathogenesis of androgen deficiency caused by T2DM. (C) 2017 Elsevier Inc. All rights reserved.