PPARα regulates the hepatotoxic biomarker alanine aminotransferase (ALT1) gene expression in human hepatocytes
PPARα regulates the hepatotoxic biomarker alanine aminotransferase (ALT1) gene expression in human hepatocytes
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DOI：
10.1016/j.taap.2008.03.007
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发表时间：
2008-08-15
影响因子：
3.8
通讯作者：
Glinghammar, Bjorn
中科院分区：
文献类型：
--
作者：
Thulin, Petra;Rafter, Ingalill;Glinghammar, Bjorn
在这项工作中，我们研究了在使用降脂药物、过氧化物酶体增殖物激活受体 (PR R) α 激动剂 AZD4619 的 I 期临床试验中观察到转氨酶水平升高背后的潜在机制。在接受 AZD4619 治疗的健康志愿者中，血清丙氨酸转氨酶 (ALT) 和天冬氨酸转氨酶 (AST) 活性升高，而其他肝损伤标志物并未增加。此前曾报道过一些接受另一种 PPAR α 激动剂非诺贝特治疗的患者出现血清转氨酶升高的情况。在随后的体外研究中，我们观察到非诺贝酸处理后人肝细胞中 ALT1 蛋白和 mRNA 的表达增加。 PPAR 对 ALT1 表达的影响通过直接转录机制发挥作用，涉及近端 ALT1 启动子中的至少一个 PPAR 反应元件 (PPRE)，而未观察到非诺贝特和 AZD4619 对 ALT2 启动子的影响。 PPAR 与位于转录起始位点 -574 bp 处的 PPRE 的结合在合成寡核苷酸和肝细胞 DNA 上得到证实。这些数据表明细胞内 ALT 表达受到 PPAR 激动剂的调节，并且这种机制可能有助于血清中 ALT 活性的增加。 (c) 2008 Elsevier Inc. 保留所有权利。
In this work, we investigated a potential mechanism behind the observation of increased aminotransferase levels in a phase I clinical trial using a lipid-lowering drug, the peroxisome proliferator-activated receptor (PR R) alpha agonist, AZD4619. In healthy volunteers treated with AZD4619, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were elevated without an increase in other markers for liver injury. These increases in serum aminotransferases have previously been reported in some patients receiving another PPAR alpha agonist, fenofibrate. In Subsequent in vitro studies, we observed increased expression of ALT1 Protein and mRNA in human hepatocytes after treatment with fenofibric acid. The PPAR effect on ALT1 expression was shown to act through a direct transcriptional mechanism involving at least one PPAR response element (PPRE) in the proximal ALT1 promoter, while no effect of fenofibrate and AZD4619 was observed on the ALT2 promoter. Binding of PPARs to the PPRE located at -574 bp from the transcriptional start site was confirmed on both synthetic oligonucleotides and DNA in hepatocytes. These data show that intracellular ALT expression is regulated by PPAR agonists and that this mechanism might contribute to increased ALT activity in serum. (c) 2008 Elsevier Inc. All rights reserved.