NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis
NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis
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DOI：
10.1128/mcb.00915-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Kensler, Thomas W.
中科院分区：
文献类型：
--
作者：
Shin, Soona;Wakabayashi, Nobunao;Kensler, Thomas W.
NF-E2 p45相关因子2（NRF 2）和芳香烃受体（AHR）是控制调节外源性物质代谢途径的转录因子。AHR最近被证明影响Nrf 2表达。相反，这项研究表明，NRF 2调节Ahr的表达，并随后调节AHR信号级联的几个下游事件，包括（i）异生物质代谢基因Cyp 1a 1和Cyp 1b 1的转录控制和（ii）抑制小鼠胚胎成纤维细胞（MEFs）中的脂肪形成。AHR的组成型表达受Nrf 2基因型的影响。此外，NRF 2信号传导的药理学激活剂CDDO-IM {1-[2-氰基-3，12-二氧代齐墩果烷-1，9（11）-二烯-28-酰基]咪唑}在Nrf 2（+/+）MEFs中诱导Ahr、Cyp 1a 1和Cyp 1b 1转录，但在Nrf 2（-/-）MEFs中不诱导。报告基因分析和染色质免疫沉淀分析表明，NRF 2直接结合到Ahr启动子-230-bp区域的一个抗氧化反应元件（ARE）。由于AHR负性控制脂肪细胞分化，我们推测NRF 2将通过与AHR途径的相互作用抑制脂肪形成。Nrf 2（-/-）MEFs在刺激后表现出明显加速的脂肪形成，而Keap 1（-/-）MEFs（表现出更高的NRF 2信号传导）与其同源野生型MEFs相比分化缓慢。在Nrf 2（-/-）MEFs中Ahr和显性阳性Nrf 2的异位表达也显著延迟了分化。因此，NRF 2直接调节AHR信号传导，突出了这些途径的双向相互作用。
The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are transcription factors controlling pathways modulating xenobiotic metabolism. AHR has recently been shown to affect Nrf2 expression. Conversely, this study demonstrates that NRF2 regulates expression of Ahr and subsequently modulates several downstream events of the AHR signaling cascade, including (i) transcriptional control of the xenobiotic metabolism genes Cyp1a1 and Cyp1b1 and (ii) inhibition of adipogenesis in mouse embryonic fibroblasts (MEFs). Constitutive expression of AHR was affected by Nrf2 genotype. Moreover, a pharmacological activator of NRF2 signaling, CDDO-IM {1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole}, induced Ahr, Cyp1a1, and Cyp1b1 transcription in Nrf2(+/+) MEFs but not in Nrf2(-/-) MEFs. Reporter analysis and chromatin immunoprecipitation assay revealed that NRF2 directly binds to one antioxidant response element (ARE) found in the -230-bp region of the promoter of Ahr. Since AHR negatively controls adipocyte differentiation, we postulated that NRF2 would inhibit adipogenesis through the interaction with the AHR pathway. Nrf2(-/-)MEFs showed markedly accelerated adipogenesis upon stimulation, while Keap1(-/-) MEFs (which exhibit higher NRF2 signaling) differentiated slowly compared to their congenic wild-type MEFs. Ectopic expression of Ahr and dominant-positive Nrf2 in Nrf2(-/-) MEFs also substantially delayed differentiation. Thus, NRF2 directly modulates AHR signaling, highlighting bidirectional interactions of these pathways.