Abstract
NF-E2-related factor 2 (NRF2), an antioxidant transcription factor, is activated in autophagy-deficient mice due to the accumulations of p62/SQSTM1 and its subsequent interaction with Kelch-like-ECH-associated protein 1 (KEAP1), an adaptor component for Cullin3-based E3 ubiquitin ligase complex. Farnesoid x receptor (FXR/NR1H4) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. FXR plays an essential role in bile acid synthesis and enterohepatic circulation, affecting glucose and lipid metabolism. Obeticholic acid as a potent FXR agonist has been approved to treat primary biliary cholangitis and clinical trials for its use in the treatment of other liver diseases are underway. Here we show that NRF2 activation in autophagy defects impedes a transactivation of FXR. Liver-specific Atg7 knockout mice or a treatment of autophagy inhibitor showed decreased inductions of FXR target genes upon its synthetic agonists. Moreover, enforced NRF2 activations with small molecules potently decreased the pharmacological activation of FXR in cultured cells. Finally, we demonstrate that NRF2 activation by the treatment with the food antioxidant butylated hydroxyanisole is necessary and sufficient to inhibit the pharmacological activation of FXR in vivo. These results reveal a novel function of the basal autophagy-NRF2 axis for the regulation of FXR transactivation, and shed light on a potential therapeutic strategy in metabolic disease.
Highlights
Received: 13 January 2022NF-E2-related factor 2 (NRF2) is a member of the “cap’n’collar” (CNC) family of DNA-binding transcription factors, featured by a conserved basic region-leucine zipper motif, CNC domain, and transactivation/transrepression domain [1,2]
Wild-type C57BL/6J mice were purchased from Japan SLC, Inc. (Japan) (C57BL/ 6JJmsSlc); Atg7F/F (RBRC02759) [43] mice were purchased from RIKEN BioResource Research Center (Japan); Alb-Cre mice [44] and Nrf2F/F mice [45,46] were purchased from the Jackson laboratory (USA); Keap1F/F mice [47] were obtained from the Masayuki
Mice were elevated during fasting or upon treatment of a synthetic PPARα agonist GW7647 but these responses were compromised in Atg7LKO mice [40], allowing us to have a hypothesis that core-autophagy-related genes play a pivotal role in functionalities of at least some of nuclear receptors, including FXR
Summary
NRF2 is a member of the “cap’n’collar” (CNC) family of DNA-binding transcription factors, featured by a conserved basic region-leucine zipper (bZIP) motif, CNC domain, and transactivation/transrepression domain [1,2]. The transcriptional activation of NRF2 requires a heterodimerization with a member of the small Maf protein family, allowing them to bind to the antioxidant or electrophile responsive element (ARE/EpRE) [3]. NRF2 controls the transcriptional programs of a series of phase 2 detoxifying genes and phase 3 transporters via ARE sites within their regulatory regions [4,5]. A yeast-two hybrid screen isolated the Kelch-like ECH-associated protein 1 (KEAP1) as an NRF2 interaction protein. As an adaptor protein for the Cullin3-based E3 ubiquitin ligase complex, KEAP1 promotes the degradation of NRF2 under unstressed conditions [13,14]
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