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Open AccessFeature PaperArticle

Influence of Liver Fibrosis on Lobular Zonation

1
Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139 Dortmund, Germany
2
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
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Faculty of Medicine, Institute of Computational Biomedicine, Heidelberg University, Bioquant—Im Neuenheimer Feld 267, 69120 Heidelberg, Germany
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Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Pauwelsstrasse 19, 52074 Aachen, Germany
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Histology Department, Faculty of Medicine, South Valley University, Qena 83523, Egypt
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Department of Histology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
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Department of Medicine III, University Hospital RWTH Aachen, Aachen University, 52074 Aachen, Germany
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Faculty of Medicine, Rudolf-Schönheimer-Institute of Biochemistry, Leipzig University, 04103 Leipzig, Germany
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Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria Paris & Sorbonne Université LJLL, 2 Rue Simone IFF, 75012 Paris, France
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(12), 1556; https://doi.org/10.3390/cells8121556
Received: 5 November 2019 / Revised: 25 November 2019 / Accepted: 28 November 2019 / Published: 2 December 2019
Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds. View Full-Text
Keywords: zonation; liver lobule; chronic liver disease; cytochrome P450; inflammation; bile duct ligation; acetaminophen zonation; liver lobule; chronic liver disease; cytochrome P450; inflammation; bile duct ligation; acetaminophen
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Ghallab, A.; Myllys, M.; H. Holland, C.; Zaza, A.; Murad, W.; Hassan, R.; A. Ahmed, Y.; Abbas, T.; A. Abdelrahim, E.; Schneider, K.M.; Matz-Soja, M.; Reinders, J.; Gebhardt, R.; Berres, M.-L.; Hatting, M.; Drasdo, D.; Saez-Rodriguez, J.; Trautwein, C.; G. Hengstler, J. Influence of Liver Fibrosis on Lobular Zonation. Cells 2019, 8, 1556.

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