Influence of Liver Fibrosis on Lobular Zonation


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.

Citation: Cells 8(12):1556 2019

Date Published: 1st Dec 2019

Registered Mode: Not specified

Authors: Ahmed Ghallab, Maiju Myllys, Christian Holland, Ayham Zaza, Walaa Murad, Reham Hassan, Yasser A Ahmed, Tahany Abbas, Eman Abdelrahim, Kai Markus Schneider, Madlen Matz-Soja, Joerg Reinders, Rolf Gebhardt, Theresa Hildegard Wirtz, Maximilian Hatting, Dirk Drasdo, Julio Saez-Rodriguez, Christian Trautwein, Jan Hengstler

help Submitter
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. (2019). Influence of Liver Fibrosis on Lobular Zonation. In Cells (Vol. 8, Issue 12, p. 1556). MDPI AG.

Views: 2419

Created: 5th Dec 2019 at 08:42

Last updated: 8th Mar 2024 at 07:44

help Tags

This item has not yet been tagged.

help Attributions


Powered by
Copyright © 2008 - 2023 The University of Manchester and HITS gGmbH