NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis

Soona Shin, Nobunao Wakabayashi, Vikas Misra, Shyam Biswal, Hwa Lee Gum, Elin S. Agoston, Masayuki Yamamoto, Thomas W. Kensler

研究成果: Article査読

244 被引用数 (Scopus)


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, Cypla1, and Cyplb1 transcription in Nrj2+/+ 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.

ジャーナルMolecular and cellular biology
出版ステータスPublished - 2007 10月

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学


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