Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.

译文

噻唑烷二酮类 (TZDs) 如吡格列酮和罗格列酮被广泛用作胰岛素增敏剂治疗2型糖尿病。在患有多囊卵巢综合征的糖尿病女性中,吡格列酮或罗格列酮治疗可改善胰岛素抵抗和高雄激素血症,但TZDs下调雄激素产生的机制尚不清楚。雄激素是在人类性腺和肾上腺中合成的。我们通过分析吡格列酮和罗格列酮对人肾上腺NCI-H295R细胞类固醇生成的影响,研究了雄激素产生的调节,这是建立的人肾上腺皮质类固醇生成的体外模型。两种tzd都改变了NCI-H295R细胞的类固醇特征,并抑制了雄激素生物合成的关键酶P450c17和3betaHSDII的活性。吡格列酮但不抑制罗格列酮抑制CYP17和HSD3B2基因的表达。同样,吡格列酮抑制了NCI-H295R细胞中CYP17和HSD3B2启动子报告基因的基础和8-溴-camp刺激的活性。然而,吡格列酮没有改变cAMP反应性荧光素酶报告基因的活性,表明它不影响cAMP/蛋白激酶a/cAMP反应元件结合蛋白途径的信号传导。尽管过氧化物酶体增殖物激活受体 γ (PPARgamma) 是TZDs的核受体,但通过小干扰RNA技术抑制PPARgamma并没有改变吡格列酮对CYP17和HSD3B2表达的抑制作用,表明吡格列酮的作用是独立于PPARgamma。另一方面,用丝裂原激活的蛋白激酶激酶 (MEK)/细胞外信号调节激酶 (ERK) 抑制剂2-(2-氨基-3-甲氧基苯基)-4h-1-苯并吡喃-4-酮 (PD98059) 处理NCI-H295R细胞增强了cyp17的启动子活性和表达。通过吡格列酮处理逆转了这种作用,表明MEK/ERK信号通路在调节吡格列酮的雄激素生物合成中起作用。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录