From the Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 and.
the Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
J Biol Chem. 2019 Feb 22;294(8):2935-2946. doi: 10.1074/jbc.RA118.005504. Epub 2018 Dec 26.
Estrogen hormones play an important role in controlling glucose homeostasis and pancreatic β-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic β-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic β-cells. We show that catechol estrogens, hydroxylated at positions C2 and C4 of the steroid A ring, rapidly potentiated glucose-induced insulin secretion via a nongenomic mechanism. 2-Hydroxyestrone, the most abundant endogenous estrogen metabolite, was more efficacious in stimulating insulin secretion than any other tested catechol estrogens. In insulin-secreting cells, catechol estrogens produced rapid activation of calcium influx and elevation in cytosolic free calcium. Catechol estrogens also generated sustained elevations in cytosolic free calcium and evoked inward ion current in HEK293 cells expressing the transient receptor potential A1 (TRPA1) cation channel. Calcium influx and insulin secretion stimulated by estrogen metabolites were dependent on the TRPA1 activity and inhibited with the channel-specific pharmacological antagonists or the siRNA. Our results suggest the role of estrogen metabolism in a direct regulation of TRPA1 activity with potential implications for metabolic diseases.
雌激素在控制葡萄糖稳态和胰岛β细胞功能方面发挥着重要作用。尽管雌激素对葡萄糖代谢的调节具有重要意义，但对于内源性雌激素代谢物在调节胰岛β细胞功能方面的作用知之甚少。在这项研究中，我们评估了主要的天然雌激素代谢物儿茶酚雌激素对胰岛β细胞胰岛素分泌的影响。我们发现，位于甾体 A 环 C2 和 C4 位羟基化的儿茶酚雌激素通过非基因组机制迅速增强葡萄糖诱导的胰岛素分泌。2-羟基雌酮是最丰富的内源性雌激素代谢物，其刺激胰岛素分泌的效力比其他测试的儿茶酚雌激素都要强。在胰岛素分泌细胞中，儿茶酚雌激素可迅速激活钙内流并增加细胞浆游离钙水平。儿茶酚雌激素还可引起持续升高的细胞浆游离钙，并在表达瞬时受体电位 A1（TRPA1）阳离子通道的 HEK293 细胞中诱发内向离子电流。雌激素代谢物刺激的钙内流和胰岛素分泌依赖于 TRPA1 活性，并可被通道特异性药理学拮抗剂或 siRNA 抑制。我们的研究结果表明，雌激素代谢在直接调节 TRPA1 活性方面发挥着作用，这可能对代谢性疾病产生影响。
