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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Adenoma, Animals, Female, Hepatocytes, Humans, Liver Neoplasms, Mice, NF-E2-Related Factor 2, NF-kappa B, Reactive Oxygen Species, Transcription Factor RelA.
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Do nF-κB/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma? Context: 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 both transcription factors on cytoprotective Nrf2 target genes. Rather, loss of Nrf2 or NF-κB/RelA altered the expression of different genes, and the combination of these alterations likely affects liver homeostasis in the double mutant mice.
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Our results provide genetic evidence for a functional cross-talk of Nrf2 and NF-κB/RelA in hepatocytes, which protects the liver from necrosis, inflammation and fibrosis. Furthermore, the double mutant mice represent a valuable animal model for iHCA. Final Decision: yes