Human Catalase Gene is Regulated by Peroxisome Proliferator Activated Receptor-gamma through a Response Element Distinct from That of Mouse
Human Catalase Gene is Regulated by Peroxisome Proliferator Activated Receptor-gamma through a Response Element Distinct from That of Mouse
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DOI：
10.1507/endocrj.k09e-113
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发表时间：
2010-04-20
影响因子：
2
通讯作者：
Shimomura, Iichiro
中科院分区：
文献类型：
--
作者：
Okuno, Yosuke;Matsuda, Morihiro;Shimomura, Iichiro
氧化应激已被认为是动脉粥样硬化、糖尿病微血管并发症以及 2 型糖尿病的 β 细胞衰竭的因果作用。 PPAR γ 激动剂不仅可以提高胰岛素敏感性，还可以消除氧化应激。在小鼠中，过氧化氢酶（一种主要的抗氧化酶）通过其启动子中的两个 PPAR γ 结合元件直接受 PPAR γ 调节。本研究探讨了人类过氧化氢酶表达的调节机制。用 PPAR γ 激动剂处理后，人原代脂肪细胞中过氧化氢酶的表达显着上调。然而，小鼠 PPAR γ 反应元件在人过氧化氢酶启动子中的功能并不保守。在含有人过氧化氢酶启动子 PPAR γ/RXR α 的荧光素酶报告基因检测中，结合 PPAR γ 激动剂，显着反式激活 19 kb 的启动子，这是通过距人过氧化氢酶基因转录起始位点 -12 kb 处的新型 PPAR γ 响应元件 (PPRE) 介导的。电泳迁移率变动分析显示 PPAR gamma 与该 PPRE 直接结合。总之，我们的结果表明，PPAR γ 通过与小鼠不同的 PPRE 调节人类过氧化氢酶基因的表达，并且至少可以部分解释观察到的 PPAR γ 对人类氧化应激的抑制作用。
Oxidative stress has been implicated as a causal role in atherosclerosis, microvascular complications of diabetes as well as in beta cell failure in type 2 diabetes. PPAR gamma agonists not only improve insulin sensitivity but also eliminate oxidative stress. In mouse, catalase, a major antioxidant enzyme, is directly regulated by PPAR gamma through two PPAR gamma binding elements in its promoter. This study examined the regulatory mechanisms of catalase expression in human. Expression of catalase was significantly upregulated in human primary adipocytes upon treatment with a PPAR gamma agonist. However, the mouse PPAR gamma response elements are not functionally conserved in human catalase promoter. In luciferase reporter assay containing human catalase promoter, PPAR gamma/RXR alpha, in combination of a PPAR gamma agonist significantly transactivated 19 kb of promoter and this was mediated via a novel PPAR gamma response element (PPRE) at -12 kb from transcription initiation site of human catalase gene. Electrophoretic mobility shift assay showed direct binding of PPAR gamma to this PPRE. Together, our results indicate that PPAR gamma regulates the expression of catalase gene in human through a PPRE distinct from that of mouse, and could explain, at least in part, the observed inhibitory effects of PPAR gamma on oxidative stress in human.