Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone:: a peroxisome proliferator-activated receptor-γ (PPARγ)-independent, antioxidant-related mechanism
Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone:: a peroxisome proliferator-activated receptor-γ (PPARγ)-independent, antioxidant-related mechanism
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DOI：
10.1016/s0006-2952(01)00764-x
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发表时间：
2001-10-15
影响因子：
5.8
通讯作者：
Roesler, WJ
中科院分区：
文献类型：
--
作者：
Davies, GF;Khandelwal, RL;Roesler, WJ
磷酸烯醇式丙酮酸羧激酶（PEPCK）是胚胎发育的限速酶。PEPCK基因在肝脏中的表达增强存在于大多数糖尿病模型中，并且被认为有助于在这种疾病中观察到的肝葡萄糖输出增加。最近，我们发现曲格列酮，第一个噻唑烷二酮（TZD）临床使用，抑制PEPCK基因在离体肝细胞的表达。我们一直在研究曲格列酮发挥这种抑制作用的分子机制。已知TZD结合并激活过氧化物酶体增殖物激活受体-γ（PPAR γ），一种调节靶基因表达的核受体。最初，我们研究了其他三种TZD（罗格列酮、恩格列酮和环格列酮）抑制PEPCK基因表达的能力。尽管这些试剂是PPAR-gamma的配体，但它们对该基因的表达几乎没有抑制活性。GW 1929 [N-（2-苯甲酰基苯基）-1-酪氨酸]是另一种在结构上与TZD无关的有效PPAR-gamma配体，对PEPCK基因表达无抑制作用，而天然PPAR-gamma配体前列腺素代谢物15-PGJ（2）（15-脱氧-Delta（12，14）-前列腺素J（2））仅显示出适度的抑制活性。用其它过氧化物酶体增殖物激活受体亚型的配体处理肝细胞对PEPCK基因表达也没有显著影响。曲格列酮含有其他TZD中不存在的α-生育酚（维生素E）部分，用维生素E处理肝细胞可抑制PEPCK基因表达。这些观察结果支持以下结论：曲格列酮通过不依赖于PPAR γ的抗氧化剂相关机制抑制PEPCK基因表达。(C)2001 Elsevier Science Inc. All rights reserved.
Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis. Enhanced expression of the PEPCK gene in liver is present in most models of diabetes, and is thought to contribute to the increased hepatic glucose output seen in this disease. Recently, we showed that troglitazone, the first thiazolidinedione (TZD) used clinically, inhibits expression of the PEPCK gene in isolated hepatocytes. We have pursued the molecular mechanism whereby troglitazone exerts this inhibition. TZDs are known to bind and activate peroxisome proliferator-activated receptor-gamma (PPAR gamma), a nuclear receptor, which regulates expression of target genes. Initially, we examined the abilities of three other TZDs (rosiglitazone, englitazone, and ciglitazone) to inhibit expression of the PEPCK gene. Despite the fact that these agents are ligands for PPAR-gamma, they displayed little if any inhibitory activity on the expression of this gene. GW1929 [N-(2-benzoyl phenyl)-1-tyrosine], another potent PPAR-gamma ligand that is unrelated structurally to TZDs, had no inhibitory effect on PEPCK gene expression, while a natural PPAR gamma ligand, the prostaglandin metabolite 15-PGJ(2) (15-deoxy-Delta (12,14)-prostaglandin J(2)), displayed only modest inhibitory activity. Treatment of hepatocytes with ligands for other isoforms of PPAR also had no significant effect on PEPCK gene expression. Troglitazone has an a-tocopherol (vitamin E) moiety that is not present in other TZDs, and treatment of hepatocytes with vitamin E led to an inhibition of PEPCK gene expression. These observations support the conclusion that troglitazone inhibits the expression of the PEPCK gene by a PPAR gamma -independent, antioxidant-related mechanism. (C) 2001 Elsevier Science Inc. All rights reserved.