Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor
Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor
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DOI：
10.1124/dmd.117.078683
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发表时间：
2018-03-01
影响因子：
3.9
通讯作者：
Daujat-Chavanieu, Martine
中科院分区：
文献类型：
--
作者：
de Boussac, Hugues;Gondeau, Claire;Daujat-Chavanieu, Martine
生长因子在肝脏生理和病理中起着关键作用，特别是通过促进细胞增殖和生长。最近，研究表明，在小鼠肝细胞中，表皮生长因子受体（EGFR）在抗癫痫药物苯巴比妥激活异种传感器组成型雄烷受体（CAR）中起着至关重要的作用。由于CAR信号的物种选择性，我们在这里研究了表皮生长因子（EGF）在人原代肝细胞中CAR信号传导中的作用。在EGF存在或不存在的情况下，将原代人肝细胞与人CAR激动剂CITCO或间接CAR激活剂苯巴比妥一起孵育。通过sirna沉默编码CAR和PXR的基因，评估了CAR依赖性基因表达调节和PXR参与这些反应。EGF显著降低了CAR的表达，阻止了CITCO的基因诱导，并在一定程度上阻止了苯巴比妥的基因诱导。在缺乏EGF的情况下，苯巴比妥和CITCO分别调节了人原代肝细胞中144和111个基因的表达。在这些基因中，只有15个由CITCO调控，1个由苯巴比妥以car依赖的方式调控。相反，当EGF存在时，CITCO和苯巴比妥仅以acar独立和pxr依赖的方式调节基因表达。总体而言，我们的研究结果表明，在原代人肝细胞中，EGF主要通过转录调控特异性抑制CAR信号传导，并通过妊娠X受体（PXR）介导的机制驱动外源反应。
Growth factors have key roles in liver physiology and pathology, particularly by promoting cell proliferation and growth. Recently, it has been shown that in mouse hepatocytes, epidermal growth factor receptor (EGFR) plays a crucial role in the activation of the xenosensor constitutive androstane receptor (CAR) by the antiepileptic drug phenobarbital. Due to the species selectivity of CAR signaling, here we investigated epidermal growth factor (EGF) role in CAR signaling in primary human hepatocytes. Primary human hepatocytes were incubated with CITCO, a human CAR agonist, or with phenobarbital, an indirect CAR activator, in the presence or absence of EGF. CAR-dependent gene expression modulation and PXR involvement in these responses were assessed upon siRNA-based silencing of the genes that encode CAR and PXR. EGF significantly reduced CAR expression and prevented gene induction by CITCO and, to a lower extent, by phenobarbital. In the absence of EGF, phenobarbital and CITCO modulated the expression of 144 and 111 genes, respectively, in primary human hepatocytes. Among these genes, only 15 were regulated by CITCO and one by phenobarbital in a CAR-dependent manner. Conversely, in the presence of EGF, CITCO and phenobarbital modulated gene expression only in aCAR-independent and PXR-dependent manner. Overall, our findings suggest that in primary human hepatocytes, EGF suppresses specifically CAR signaling mainly through transcriptional regulation and drives the xenobiotic response toward a pregnane X receptor (PXR)-mediated mechanism.