**1. Introduction**

Prevalence and mortality of liver diseases, including fibrosis and cirrhosis, continue to grow in Europe [1]. The increase in alcohol consumption and obesity-associated non-alcoholic fatty liver disease (NAFLD) in recent years has contributed to this development. 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 [3–5]. Progressive fibrosis is characterized by the excessive accumulation of the extracellular matrix which compromises the functional architecture of the organ [3,6].

Liver zonation is the spatial separation of a large spectrum of different metabolic pathways along the porto-central axis of the liver lobule, which is essential for liver function [7,8]. For example, xenobiotic metabolism by cytochrome P450 enzymes (CYP) is located in the approximately 50% of hepatocytes in the center of the liver lobule [9,10]. This serves to detoxify xenobiotics before they are drained into the central vein [2,11]. However, for compounds metabolically activated by CYPs, such as CCl4 or acetaminophen, the zonated expression causes a pericentral pattern of necrosis [12,13]. A zonated metabolic pattern is also known for ammonia metabolism [14]. While urea-cycle enzymes detoxify ammonia by high capacity and low affinity mechanism in the periportal and midzonal regions, low remaining ammonia concentrations are removed from the sinusoidal blood by a pericentral ring of glutamine synthetase positive hepatocytes that act by a low capacity, high affinity mechanism [15–17]. Further zonated functions include glycolysis, gluconeogenesis, glycogenesis, the TCA-cycle, glutamine metabolism and lipogenesis [2,7].

While liver fibrosis and the mechanisms of zonation have already been intensively studied [18–21], little is known about how liver fibrosis influences lobular zonation. In the present study, we used three different mouse models of liver fibrosis, chronic CCl4 intoxication, bile duct ligation (BDL) and the knockout of mdr2. For all three fibrosis models, we observed a loss of pericentral factors, while the entire lobule adapts periportal features. Besides of several adverse consequences, 'periportalization' is responsible for adaptation to toxic stress during the pathogenesis of liver fibrosis and leads to resistance to the hepatotoxic compound acetaminophen (APAP).
