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

Journal of Hepatology
Ulrike A KöhlerSabine Werner

Abstract

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-κB regulate the cellular antioxidant defense system and important survival pathways, we determined their individual and overlapping functions in the liver. We generated mice lacking Nrf2 and the NF-κB 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. Loss of either Nrf2 or NF-κB/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-κB RelA/p65 was not detectable in the nuclei of iHCA tumor cells. The mouse phenotype was not due to a synergistic effect of bo...Continue Reading

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Citations

Mar 10, 2016·Oxidative Medicine and Cellular Longevity·Regina MedvedevEberhard Hildt
Jan 27, 2016·Human Vaccines & Immunotherapeutics·Janina E Linnik, Adrian Egli
Jan 31, 2018·Nature Reviews. Immunology·Koji Taniguchi, Michael Karin
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Jan 16, 2020·Molecular Cancer·Zhonghua MaJiafu Ji

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