A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells
A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells
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含有核受体和长非编码 RNA 的转录调控网络控制 HepaRG 细胞中细胞色素 P450 的基础表达和药物诱导表达
DOI：
10.1124/mol.118.112235
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发表时间：
2018-07-01
影响因子：
3.6
通讯作者：
Zhong, Xiao-bo
中科院分区：
文献类型：
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作者：
Chen, Liming;Bao, Yifan;Zhong, Xiao-bo
细胞色素P450（P450）酶负责代谢药物。P450的表达可直接影响药物的代谢，导致疗效和不良反应的不同结果。几种核受体是可以在基础水平和药物诱导水平上调节P450表达的转录因子。转录因子附近的一些长链非编码RNA（lncRNA）参与转录因子的调控功能。本研究的目的是确定是否有一个转录调控网络包含核受体和lncRNA控制基础和药物诱导的HepaRG细胞中P450的表达。应用小干扰RNA或小发夹RNA敲低四种核受体[肝细胞核因子1 α（HNF 1 α），肝细胞核因子4 α（HNF 4 α），β-羟色胺X受体（PXR），和组成型雄烷受体（CAR）]以及两种lncRNA [HNF 1a反义RNA 1 HNF 1 α-AS 1和HNF 4 α反义RNA 1（HNF 4 α-AS 1）]在有或无苯巴比妥或利福平处理的HepaRG细胞中的表达。在基础水平和药物诱导水平下检测8种P450酶的表达。CAR和PXR主要调节特异性P450的表达。HNF 1 α和HNF 4 α影响广泛的P450和其他转录因子的表达。HNF 1 α和HNF 4 α分别控制其邻近lncRNA HNF 1 α-AS 1和HNF 4 α-AS 1的表达。HNF 1 α-AS 1和HNF 4 α-AS 1也以不同方式参与P450和转录因子的调节。总之，我们的研究得出结论，一个包含核受体和lncRNA的转录调控网络控制HepaRG细胞中P450的基础和药物诱导的表达。
Cytochrome P450 (P450) enzymes are responsible for metabolizing drugs. Expression of P450s can directly affect drug metabolism, resulting in various outcomes in therapeutic efficacy and adverse effects. Several nuclear receptors are transcription factors that can regulate expression of P450s at both basal and drug-induced levels. Some long noncoding RNAs (lncRNAs) near a transcription factor are found to participate in the regulatory functions of the transcription factors. The aim of this study is to determine whether there is a transcriptional regulatory network containing nuclear receptors and lncRNAs controlling both basal and drug-induced expression of P450s in HepaRG cells. Small interfering RNAs or small hairpin RNAs were applied to knock down four nuclear receptors [hepatocyte nuclear factor 1 alpha (HNF1 alpha), hepatocyte nuclear factor 4 alpha (HNF4 alpha), pregnane X receptor (PXR), and constitutive androstane receptor (CAR)] as well as two lncRNAs [HNF1a antisense RNA 1 (HNF1 alpha-AS1) and HNF4 alpha antisense RNA 1 (HNF4 alpha-AS1)] in HepaRG cells with or without treatment of phenobarbital or rifampicin. Expression of eight P450 enzymes was examined in both basal and drug-induced levels. CAR and PXR mainly regulated expression of specific P450s. HNF1 alpha and HNF4 alpha affected expression of a wide range of P450s as well as other transcription factors. HNF1 alpha and HNF4 alpha controlled the expression of their neighborhood lncRNAs, HNF1 alpha-AS1 and HNF4 alpha-AS1, respectively. HNF1 alpha-AS1 and HNF4 alpha-AS1 was also involved in the regulation of P450s and transcription factors in diverse manners. Altogether, our study concludes that a transcription regulatory network containing the nuclear receptors and lncRNAs controls both basal and drug-induced expression of P450s in HepaRG cells.