NF-κB/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma

Background & Aims: The liver is frequently challenged by toxins and reactive oxygen species. Therefore, hepatocytes require cytoprotective strategies to cope with these insults. Since the transcription factors Nrf2 and NF-kappa B regulate the cellular antioxidant defense system and important survival pathways, we determined their individual and overlapping functions in the liver. Methods: We generated mice lacking Nrf2 and the NF-kappa B RelA/p65 subunit in hepatocytes and we analyzed their liver by using histopathology, immunohistochemistry, quantitative RT-PCR, Western blot and Oxyblot analysis. Human inflammatory hepatocellular adenomas (iHCA) were analyzed by immunohistochemistry. Results: Loss of either Nrf2 or NF-kappa B/RelA had only a minor effect on liver homeostasis, but the double knockout mice spontaneously developed liver inflammation and fibrosis. Upon aging, more than one-third of the female double mutant mice developed tumors, which histologically resemble human iHCA, a tumor that predominantly occurs in women. The mouse tumors also recapitulated the immunohistochemical marker profile characteristic for human iHCA. Moreover, pNRF2 and NF-kappa B RelA/p65 was not detectable in the nuclei of iHCA tumor cells. The mouse phenotype was not due to a synergistic effect of both transcription factors on cytoprotective Nrf2 target genes. Rather, loss of Nrf2 or NF-kappa B/RelA altered the expression of different genes, and the combination of these alterations likely affects liver homeostasis in the double mutant mice. Conclusions: Our results provide genetic evidence for a functional cross-talk of Nrf2 and NF-kappa B/RelA in hepatocytes, which protects the liver from necrosis, inflammation and fibrosis. Furthermore, the double mutant mice represent a valuable animal model for iHCA. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.