MCB Accepts, published online ahead of print on 20 August 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00915-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

NRF2 modulates AHR signaling: influence on adipogenesis

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

Department of Pharmacology and Molecular Sciences, School of Medicine, Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA, Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennoudai, Tsukuba 305-8577, Japan

^* To whom correspondence should be addressed. Email: tkensler{at}jhsph.edu.

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 metabolizing 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) induced Ahr, Cyp1a1 and Cyp1b1 transcription in Nrf2^+/+ but not in Nrf2^-/- MEFs. Reporter analysis and ChIP 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.

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