Dehydroepiandrosterone Inhibits Glucose Flux Through the Pentose Phosphate Pathway in Human and Mouse Endometrial Stromal Cells, Preventing Decidualization and Implantation
Dehydroepiandrosterone Inhibits Glucose Flux Through the Pentose Phosphate Pathway in Human and Mouse Endometrial Stromal Cells, Preventing Decidualization and Implantation
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DOI：
10.1210/me.2011-0026
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发表时间：
2011-08-01
影响因子：
--
通讯作者：
Moley, Kelle H.
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文献类型：
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作者：
Frolova, Antonina I.;O'Neill, Kathleen;Moley, Kelle H.
子宫内膜基质细胞（ESC）必须经历胚胎驱动的分化才能形成蜕膜细胞，这是胚胎着床的必要条件。我们实验室最近的研究表明，蜕膜化细胞需要葡萄糖转运蛋白1的表达和葡萄糖使用的增加来完成这一步骤。目前的研究重点是葡萄糖依赖的分子和代谢途径，这是所需的ESC蜕膜化。抑制糖酵解对蜕膜化没有影响。然而，用药理学抑制剂6-氨基烟酰胺或脱氢表雄酮（DHEA）阻断磷酸戊糖途径（PPP），以及短发夹RNA介导的葡萄糖-6-磷酸脱氢酶（PPP中的限速步骤）的敲低，均导致体外蜕膜标记物表达的强烈下降和体内蜕膜化的减少。此外，研究表明，抑制是由于，至少部分是由于核糖-5-磷酸消耗，因为外源性核苷给药恢复了这些细胞中的蜕膜化。PPP抑制阻止ESC蜕膜化的发现是新颖的且具有临床重要性，因为DHEA是由肾上腺产生的内源性激素，并且在患有多囊卵巢综合征的高比例女性中升高，多囊卵巢综合征是育龄女性中最常见的内分泌病。总之，这些数据表明DHEA水平增加，通过PPP使用葡萄糖和妊娠丢失之间存在机械联系。（分子内分泌学25：1444-1455，2011）
Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss. (Molecular Endocrinology 25: 1444-1455, 2011)