Universität zu Köln

Koehler, Ulrike A., Boehm, Friederike, Rolfs, Frank, Egger, Michele, Hornemann, Thorsten, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Weber, Achim and Werner, Sabine (2016). NF-kappa B/RelA and Nrf2 cooperate to maintain hepatocyte integrity and to prevent development of hepatocellular adenoma. J. Hepatol., 64 (1). S. 94 - 103. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1600-0641

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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-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koehler, Ulrike A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehm, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Rolfs, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Egger, Michele UNSPECIFIED UNSPECIFIED UNSPECIFIED Hornemann, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Weber, Achim UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-292861
DOI:	10.1016/j.jhep.2015.08.033
Journal or Publication Title:	J. Hepatol.
Volume:	64
Number:	1
Page Range:	S. 94 - 103
Date:	2016
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1600-0641
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDUCED LIVER-INJURY; GENE-EXPRESSION; TRANSCRIPTION FACTORS; SIGNALING PATHWAY; INDUCED APOPTOSIS; OXIDATIVE STRESS; PROSTATE-CANCER; CELLS; REGENERATION; ACTIVATION Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/29286