Troglitazone inhibits expression of the phosphoenolpyruvate carboxykinase gene by an insulin-independent mechanism
Troglitazone inhibits expression of the phosphoenolpyruvate carboxykinase gene by an insulin-independent mechanism
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DOI：
10.1016/s0167-4889(99)00080-4
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发表时间：
1999-08-12
影响因子：
5.1
通讯作者：
Roesler, WJ
中科院分区：
文献类型：
--
作者：
Davies, GF;Khandelwal, RL;Roesler, WJ
曲格列酮是一种口服胰岛素增敏药物，用于治疗2型糖尿病患者。这种高血糖状态的一个主要特征是肝硬化发生率增加，曲格列酮能够改善这种情况。在这项研究中，我们研究了曲格列酮的这种性质的分子基础，探索这种化合物对表达的两个基因编码的主要调控酶的肝细胞生成，磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6）在原代培养的大鼠肝细胞。胰岛素能够抑制这两个基因的表达，这在我们的模型系统中得到了验证。曲格列酮显着降低PEPCK和G6 β mRNA水平的大鼠肝细胞分离正常和Zucker-diabetes大鼠，但在较小程度上观察到的胰岛素。有趣的是，曲格列酮不能降低cAMP诱导的PEPCK mRNA水平，这表明曲格列酮对基因表达产生影响的分子机制与胰岛素不同。这进一步得到了以下观察结果的支持：在存在胰岛素信号传导途径抑制剂渥曼青霉素、雷帕霉素和PD 98059的情况下，曲格列酮能够降低PEPCK mRNA水平。这些结果表明，曲格列酮可以调节特定基因的表达，在一个胰岛素非依赖性的方式，和基因编码的促血管生成酶是这种药物的抑制作用的目标。(C)1999 Elsevier Science B. V.保留所有权利。
Troglitazone is an oral insulin-sensitizing drug used to treat patients with type 2 diabetes. A major feature of this hyperglycemic state is the presence of increased rates of hepatic gluconeogenesis, which troglitazone is able to ameliorate. In this study, we examined the molecular basis for this property of troglitazone by exploring the effects of this compound on the expression of the two genes encoding the major regulatory enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary cultures of rat hepatocytes. Insulin is able to inhibit expression of both of these genes, which was verified in our model system. Troglitazone significantly reduced mRNA levels of PEPCK and G6Pase in rat hepatocytes isolated from normal and Zucker-diabetic rats, but to a lesser extent than that observed with insulin. Interestingly, troglitazone was unable to reduce cAMP-induced levels of PEPCK mRNA, suggesting that the molecular mechanism whereby troglitazone exerted its effects on gene expression differed from that of insulin. This was further supported by the observation that troglitazone was able to reduce PEPCK mRNA levels in the presence of the insulin signaling pathway inhibitors wortmannin, rapamycin, and PD98059. These results indicate that troglitazone can regulate the expression of specific genes in an insulin-independent manner, and that genes encoding gluconeogenic enzymes are targets for the inhibitory effects of this drug. (C) 1999 Elsevier Science B.V. All rights reserved.