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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
Ulrike A
UA
Köhler
Institute of Surgical Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
Friederike
F
Böhm
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
Frank
F
Rolfs
Institute of Surgical Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
Michèle
M
Egger
Institute of Clinical Chemistry, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
Thorsten
T
Hornemann
Institute for Genetics, University of Cologne, D-50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, D-50931 Cologne, Germany.
Manolis
M
Pasparakis
Institute of Surgical Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: achim.weber@usz.ch.
Achim
A
Weber
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland. Electronic address: sabine.werner@biol.ethz.ch.
Sabine
S
Werner
D000236:Adenoma / Q000517:prevention & control*; D000818:Animals; D005260:Female; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000502:physiology*
D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051996:Transcription Factor RelA
Hepatocellular adenoma; Inflammation; Liver fibrosis; NF-κB; Nrf2