Ulrike A Köhler1, Friederike Böhm2, Frank Rolfs1, Michèle Egger2, Thorsten Hornemann3, Manolis Pasparakis4, Achim Weber5, Sabine Werner6. 1. Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland. 2. Institute of Surgical Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland. 3. Institute of Clinical Chemistry, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland. 4. 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. 5. Institute of Surgical Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: achim.weber@usz.ch. 6. 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.
Abstract
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-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.
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-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. Humaninflammatory 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 mousetumors 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.
Authors: Diamantis I Tsilimigras; Amir A Rahnemai-Azar; Ioannis Ntanasis-Stathopoulos; Maria Gavriatopoulou; Demetrios Moris; Eleftherios Spartalis; Jordan M Cloyd; Sharon M Weber; Timothy M Pawlik Journal: J Gastrointest Surg Date: 2018-08-14 Impact factor: 3.452
Authors: Qingshan Chen; Hai Zhang; Yan Cao; Ying Li; Sen Sun; Junping Zhang; Guoqing Zhang Journal: Drug Des Devel Ther Date: 2017-07-26 Impact factor: 4.162