Influence of Liver Fibrosis on Lobular Zonation.

Ahmed Ghallab,Marie-Luise Berres,Julio Saez-Rodriguez,Ayham Zaza,Rolf Gebhardt,Christian H Holland,Christian Trautwein,Dirk Drasdo,Tahany Abbas,Maximilian Hatting,Yasser A Ahmed,Maiju Myllys,Walaa Murad,Jörg Reinders,Jan G Hengstler,Madlen Matz-Soja,Eman A Abdelrahim,Reham Hassan,Kai Markus Schneider

doi:10.3390/cells8121556

Abstract

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.

Highlights

Prevalence and mortality of liver diseases, including fibrosis and cirrhosis, continue to grow in Europe [1]
A principal component analysis (PCA) of the RNA-seq data showed a good clustering of each group of six mice (Figure 2B)
Treatment with CCl4 caused a shift in the inverse direction of principal component 1 (PC1) that explains ~30% of the variance in the data (Figure 2B)

Summary

Introduction

Prevalence and mortality of liver diseases, including fibrosis and cirrhosis, continue to grow in Europe [1]. Liver fibrosis is a complex wound-healing process that leads to inflammation and scarring [2,3]. It occurs as a consequence of chronic liver damage, caused by different etiologies, including chronic intoxication, viral infections, genetic diseases, or metabolic disorders due to super-nutrition [2]. Liver fibrosis requires the interaction of several cell types, myofibroblasts, macrophages, hepatocytes and immune cells that are orchestrated by a spectrum of cytokines, chemokines and mediators such as lipids, hormones and reactive oxygen species [3,4,5]. Progressive fibrosis is characterized by the excessive accumulation of the extracellular matrix which compromises the functional architecture of the organ [3,6]

Methods

Results

Conclusion