(4Z,15Z)-Octadecadienoic acid inhibits glycogen synthase kinase-3β and glucose production in H4IIE cells.
(4Z,15Z)-Octadecadienoic acid inhibits glycogen synthase kinase-3β and glucose production in H4IIE cells.
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(4Z,15Z)-十八碳二烯酸抑制 H4IIE 细胞中糖原合成酶激酶 3β 和葡萄糖的产生。
DOI：
10.1007/s11745-017-4236-3
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发表时间：
2017
期刊：
影响因子：
1.9
通讯作者：
Kawashima H.
中科院分区：
文献类型：
--
作者：
Yoshida J.;Uesugi S.;Kawamura T.;Kimura K.;Hu D.;Xia S.;Toyooka N.;Ohnishi M.;Kawashima H.
帽贝性腺中存在许多罕见的非亚甲基间断脂肪酸（NMI FA），但它们的生物学特性仍然未知。为了研究天然存在的 NMI FA 在真核细胞中的新生物效应，通过使用基于酵母的药物筛选系统，使用 Ca2+ 敏感突变株酵母，检查了结构类似的 (4Z,15Z)-十八碳二烯酸 (1)、(9Z,20Z)-二十二碳二烯酸 (2) 和 (12Z,23Z)-六碳二烯酸 (3) 的生物活性。酿酒酵母（zds1Δerg3Δpdr1Δpdr3Δ）。在 1–3 中，1 在突变酵母菌株中，在剂量为 80 µg/圆盘时显示出恢复的生长活性。该表型表明，1 通过抑制糖原合成酶激酶-3β (GSK-3β) 或钙调磷酸酶途径或同时抑制两者，从而抑制突变酵母的 Ca2+ 信号传导。由此结果，进一步确定了 1–3 对 GSK-3β 的抑制活性。1–3 对 GSK-3β 显示出有效的抑制活性，IC50 值范围为 8.7 至 21.9 µM。 GSK-3β 的抑制会降低肝脏中糖异生关键酶的基因表达，因此我们分析了大鼠肝癌 H4IIE 细胞中的葡萄糖产生，以评估 1-3 的 GSK-3β 抑制活性。 Acid1 在 H4IIE 细胞中以 25 µM 浓度抑制葡萄糖产生。我们的结果将为 1 的抗糖尿病作用开辟新的可能性，并可能为理解天然 NMI FA 的生物学特性提供重要的见解。
Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological effects of naturally occurring NMI FA in eukaryotic cells, the biological activities of structurally analogous (4Z,15Z)-octadecadienoic acid (1), (9Z,20Z)-tricosadienoic acid (2), and (12Z,23Z)-hexacosadienoic acid (3) were examined by using a yeast-based drug-screening system using the Ca2+-sensitive mutant strain,Saccharomyces cerevisiae(zds1Δerg3Δpdr1Δpdr3Δ). Among1–3,1showed restored growth activity at a dose of 80 µg/disc in the mutant yeast strain. This phenotype suggests that1suppresses Ca2+-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3β (GSK-3β) or calcineurin pathways or both. From this result, the inhibitory activity of1–3against GSK-3β was further determined.1–3showed potent inhibitory activity against GSK-3β with IC50values ranging from 8.7 to 21.9 µM. Inhibition of GSK-3β reduces gene expression of the gluconeogenic key enzymes in liver, so we analyzed glucose production in rat hepatoma H4IIE cells to assess GSK-3β inhibitory activity of1–3. Acid1inhibited glucose production at 25 µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of1and might provide important insights into understanding the biological properties of naturally occurring NMI FA.