2.3.2. Surgery-Based Injury Models

In mice, ligation of the common bile duct causes obstructive cholestatic injury and periportal fibrosis [82,83]. This procedure, known as bile duct ligation (BDL), provokes time-dependent morphological and structural changes, which is combined with elevated serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (γ-GT), alkaline phosphatase (AP), and lactate dehydrogenase (LDH) [82]. Over time, ongoing liver damage is reflected in jaundice. Besides the typical markers that reflect inflammation and fibrogenesis, the large subset of cytokeratins that can be detected by immunohistochemistry reflects the occurrence of the ductular reaction. This model is often taken to recapitulate diverse forms of human congenital and acquired cholestasis.

### 2.3.3. Genetic Models

A plenitude of genetically-modified models in which genes are overexpressed or silenced, or in which special transgenes allow sophisticated cell fate tracing experiments, are frequently used [86,87]. Prototypically, mice carrying a homozygous disruption of the *Mdr2* gene encoding the multidrug resistance 2 protein (a drug-transporting P-glycoprotein) develop a liver disease that appears to be caused by the complete inability of the liver to secrete phospholipids into the bile [85]. This results

in an accumulation of toxic bile acids in the biliary canaliculus, which damages hepatocytes and cholangiocytes, subsequently inducing liver inflammation. This model is therefore ideally suited to analyze human diseases that are associated with alterations in bile acid flow or synthesis, such as primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC).

2.3.4. Mouse Models in Translational Research of Human Liver Diseases

The above-mentioned animal models have become increasingly popular in recent years. In particular, each model is taken by investigators to analyze different aspects of human liver disease ranging from intoxication, inflammation, liver damage, liver failure, NAFLD/NASH, ASH, fibrosis, cirrhosis, hepatocellular carcinoma, cholestatic liver disease, to liver regeneration (Figure 1).

**Figure 1.** Mouse models mimicking human liver disease. The application of different hepatotoxins, feeding of special diets, and the execution of surgical procedures in mice are extensively used to explore basic pathophysiological mechanisms of human hepatic disease. In addition to these treatments, transgenic, knockout, and knock-in mice serve as tools to gain insight into human liver disease. Abbreviations used are: APAP, *N*-acetyl-p-aminophenol (acetaminophen); ASH, alcoholic steatohepatitis; BCG, bacillus Calmette–Guérin; BDL, bile duct ligation; CCl4, carbon tetrachloride; CD, choline-deficient; Con A, Concanavalin A; DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; D-GalN, D-galactosamine; DEN, diethylnitrosamine; DMN, dimethylnitrosamine; LDC, Lieber-DeCarli; LPS, lipopolysaccharide; MCD, methionine- and choline-deficient; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TAA, thioacetamide.

A study comparing mouse models of inflammation with the corresponding human disease demonstrated that studying disease in patients is generally much more complex than studying experimental model systems, suggesting that the extrapolation of preclinical data to the human situation must be critically questioned [88]. However, despite this partly justified criticism, animal models in hepatology research are still invaluable tools in understanding molecular pathological aspects in the initiation and progression of liver disease.
