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首页> 外文期刊>Molecular and Cellular Biology >NRF2 Modulates Aryl Hydrocarbon Receptor Signaling: Influence on Adipogenesis
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NRF2 Modulates Aryl Hydrocarbon Receptor Signaling: Influence on Adipogenesis

机译：NRF2调节芳烃受体信号：对脂肪形成的影响

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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.
机译：NF-E2 p45相关因子2（NRF2）和芳烃受体（AHR）是控制外源生物代谢途径的转录因子。最近显示AHR影响 Nrf2 表达。相反，这项研究表明NRF2调节 Ahr 的表达，并随后调节AHR信号级联反应的多个下游事件，包括（i）异种代谢基因 Cyp1a1 和 Cyp1b1 和（ii）抑制小鼠胚胎成纤维细胞（MEF）的脂肪生成。 AHR的组成型表达受 Nrf2 基因型的影响。此外，NRF2信号传导的药理激活剂CDDO-IM {1- [2-氰基-3,12-二氧代油橄榄-1,9（11）-二烯-28-酰基]咪唑}诱导了 Ahr，Cyp1a1 < / em>和 Cyp1b1 在 Nrf2 + / + MEF中转录，但在 Nrf2 中不是吗？/ ？ MEF。记者分析和染色质免疫沉淀分析表明，NRF2直接与 Ahr 启动子的230-bp区域中发现的一种抗氧化剂反应元件（ARE）结合。由于AHR负面控制脂肪细胞的分化，我们推测NRF2将通过与AHR途径的相互作用抑制脂肪生成。 Nrf2 ？/？ MEF在刺激后显示出明显加速的脂肪生成，而 Keap1 ？/？ MEF（表现出更高的NRF2信号）与其同质野生型MEF相比分化缓慢。在 Nrf2 ？/？ MEF中 Ahr 和显性阳性 Nrf2 的异位表达也大大延迟了分化。因此，NRF2直接调节AHR信号传导，突出显示这些途径的双向相互作用。

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