Down-regulation of acyl-CoA oxidase gene expression in heart of troglitazone-treated mice through a mechanism involving chicken ovalbumin upstream promoter transcription factor II
Down-regulation of acyl-CoA oxidase gene expression in heart of troglitazone-treated mice through a mechanism involving chicken ovalbumin upstream promoter transcription factor II
复制标题
DOI：
10.1124/mol.64.3.764
复制
发表时间：
2003-09-01
影响因子：
3.6
通讯作者：
Vázquez-Carrera, M
中科院分区：
文献类型：
--
作者：
Cabrero, A;Jové, M;Vázquez-Carrera, M
参与脂肪酸代谢的基因的心脏表达可能会根据底物的可用性而发生改变。我们研究了曲格列酮（一种选择性激活过氧化物酶体增殖物激活受体γ（PPARγ）的抗糖尿病药物）如何影响其中几个基因的表达。单日曲格列酮给药（100 mg/kg/天）不会显着改变血浆游离脂肪酸或甘油三酯水平。相比之下，曲格列酮治疗 10 天后，血浆游离脂肪酸和甘油三酯水平分别显着降低 74% (P < 0.001) 和 56% (P < 0.01)。曲格列酮治疗 1 天后，心脏酰基辅酶 A 氧化酶 (ACO) mRNA 表达增加（诱导 8.3 倍），而治疗 10 天后，ACO mRNA 水平显着降低（降低 98%，P < 0.02），解偶联蛋白 3 的 mRNA 水平也显着降低（降低 41%，P = 0.05）。曲格列酮治疗 10 天后，PPARα 和几个 PPAR 靶基因（如中链酰基辅酶 A 脱氢酶或脂肪酸转位酶）的 mRNA 表达没有改变，而肌肉型肉碱棕榈酰转移酶 I 增加了 1.7 倍（ P < 0.05）。曲格列酮治疗 10 天的小鼠心脏中 ACO 表达减少，同时转录抑制因子鸡卵清蛋白上游启动子转录因子 II (COUP-TF II) 的蛋白质水平增加。使用 COUP-TF II 抗体进行电泳迁移率变动分析，以检查其与标记的过氧化物酶体增殖物反应元件探针的相互作用，结果显示，曲格列酮治疗小鼠的心脏核提取物中 COUP-TFII 的结合增强，持续 10 天，但在对照核提取物中则没有增强。总体而言，本文提出的研究结果表明，10 天的曲格列酮治疗通过涉及转录抑制子 COUP-TF II 的机制降低了 ACO 基因的表达。
Cardiac expression of genes involved in fatty acid metabolism may suffer alterations depending on the substrate availability. We studied how troglitazone, an antidiabetic drug that selectively activates peroxisome proliferator-activated receptor gamma (PPARgamma), affected the expression of several of these genes. A single-day troglitazone administration ( 100 mg/kg/day) did not significantly alter plasma free fatty acids or triglyceride levels. In contrast, a 10-day period of troglitazone treatment significantly reduced plasma free fatty acids and triglyceride levels by 74% ( P < 0.001) and 56% ( P < 0.01), respectively. Cardiac mRNA expression of acyl-CoA oxidase (ACO) increased (8.3-fold induction) after 1-day troglitazone treatment, whereas after 10 days of treatment ACO mRNA levels were dramatically reduced (98% reduction, P < 0.02), as well as those of uncoupling protein 3 (41% reduction, P = 0.05). The mRNA expression of PPARα and several PPAR target genes, such as medium chain acyl-CoA dehydrogenase or fatty acid translocase were not altered after 10 days of troglitazone treatment, whereas muscle-type carnitine palmitoyltransferase I increased 1.7-fold ( P < 0.05). The reduction in ACO expression in the hearts of 10-day troglitazone-treated mice was accompanied by an increase in the protein levels of the transcriptional repressor chicken ovalbumin upstream promoter transcription factor II (COUP-TF II). Electrophoretic mobility shift assays performed with COUP-TF II antibody to examine its interaction with a labeled peroxisome proliferator response element probe showed enhanced binding of COUP-TFII in cardiac nuclear extracts from troglitazone-treated mice for 10 days but not in the control nuclear extracts. Overall, the findings presented here show that 10 days of troglitazone treatment decreased expression of the ACO gene through a mechanism involving the transcriptional repressor COUP-TF II.