Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes
Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes
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DOI：
10.1016/j.bbagrm.2016.03.007
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发表时间：
2016-09-01
影响因子：
4.7
通讯作者：
Zanger, Ulrich M.
中科院分区：
文献类型：
--
作者：
Kandel, Benjamin A.;Thomas, Maria;Zanger, Ulrich M.
配体激活的核受体雄烷X受体（PXR，NR1I2）和组成型雄烷受体（CAR，NR1I3）是许多重要的药物代谢酶和转运基因（DMET）对包括许多药物在内的外源性物质应答的两个主要转录调节因子。过氧化物酶体增殖物激活受体α（PPAR α，NR1C1）是贝特类降脂药物的靶点，主要调节脂肪酸代谢和能量稳态。最近的研究表明，这些受体的调控基因有很大的重叠。例如，CAR和PXR还调节参与脂质和葡萄糖代谢的关键酶的转录，PPARa还充当重要DMET基因（包括细胞色素P450的CYP 3A 4和CYP 2C 8）的直接转录调节因子。尽管它们对肝脏代谢具有重要和广泛的影响，但比较数据很少，特别是在全球一级和人类中。本研究的主要目的是直接比较原代人肝细胞中这三种核受体激活所阐明的全基因组转录变化。用CAR（CITCO）、PXR（利福平）和PPARa（WY14，643）的原型配体或作为媒介物对照的DMSO处理来自六个个体供体的培养物。全基因组的mRNA表达谱确定与Affyssin微阵列进行了分析，差异表达的基因和代谢功能。结果证实了已知的原型靶基因，并揭示了强烈重叠的共调节，但也明显调节和新的响应基因和途径。结果进一步说明了PPARa作为药物代谢调节剂的作用以及异种传感器PXR和CAR在脂质代谢和能量稳态中的作用。这篇文章是特刊的一部分，题为：异生物核受体：老狗的新技巧，由谢文博士编辑。(C)2016爱思唯尔B.V.保留所有权利。
The ligand-activated nuclear receptor pregnane X receptor (PXR, NR1I2) and the constitutive androstane receptor (CAR, NR1I3) are two master transcriptional regulators of many important drug metabolizing enzymes and transporter genes (DMET) in response to xenobiotics including many drugs. The peroxisome proliferator-activated receptor alpha (PPAR alpha, NR1C1), the target of lipid lowering fibrate drugs, primarily regulates fatty acid catabolism and energy-homeostasis. Recent research has shown that there are substantial overlaps in the regulated genes of these receptors. For example, both CAR and PXR also modulate the transcription of key enzymes involved in lipid and glucose metabolism and PPARa also functions as a direct transcriptional regulator of important DMET genes including cytochrome P450s CYP3A4 and CYP2C8. Despite their important and widespread influence on liver metabolism, comparative data are scarce, particularly at a global level and in humans. The major objective of this study was to directly compare the genome-wide transcriptional changes elucidated by the activation of these three nuclear receptors in primary human hepatocytes. Cultures from six individual donors were treated with the prototypical ligands for CAR (CITCO), PXR (rifampicin) and PPARa (WY14,643) or DMSO as vehicle control. Genomewide mRNA profiles determined with Affymetrix microarrays were analyzed for differentially expressed genes and metabolic functions. The results confirmed known prototype target genes and revealed strongly overlapping sets of coregulated but also distinctly regulated and novel responsive genes and pathways. The results further specify the role of PPARa as a regulator of drug metabolism and the role of the xenosensors PXR and CAR in lipid metabolism and energy homeostasis. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. (C) 2016 Elsevier B.V. All rights reserved.