Animal models of biliary injury and altered bile acid metabolism

Abstract

In the last 25 years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC, α-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed. Overall, they have led to a range of liver phenotypes recapitulating the main features of biliary injury and altered bile acid metabolisms, such as ductular reaction, peribiliary inflammation and fibrosis, obstructive cholestasis and biliary dysgenesis. Although with a limited translability to the human setting, these mouse models have provided us with the ability to probe over time the fundamental mechanisms promoting cholestatic disease progression. Moreover, recent studies from genetically engineered mice have unveiled ‘core’ pathways that make the cholangiocyte a pivotal player in liver repair. In this review, we will highlight the main phenotypic features, the more interesting peculiarities and the different drawbacks of these mouse models.

H19 Is Expressed in Hybrid Hepatocyte Nuclear Factor 4α+ Periportal Hepatocytes but Not Cytokeratin 19+ Cholangiocytes in Cholestatic Livers

“…C). Prior studies revealed co‐IF of CK19 and desmin of ductular structures within the portal field . We found high labeling efficiency of desmin + periportal mesenchymal cells in DRs.…”

“…Prior studies revealed co-IF of CK19 and desmin of ductular structures within the portal field. (24) We found high labeling efficiency of desmin + periportal mesenchymal cells in DRs. Colabeling with α-smooth muscle action (α-SMA) also failed to detect the presence of H19RNA in α-SMA + cells (not shown).…”

“…Conflicting results have been reported about the identity of LSCs. Recent reports in adult mice showed two distinct subpopulations of hepatocytes, namely “Axin2 + ” cells located pericentrally and “SOX9 + hybrid periportal hepatocytes” located periportally within the liver lobule …”

“…The liver toxin DDC-enriched diet is commonly used as a chemically induced chronic cholestatic liver injury model with a strong expansion of atypical ductal proliferation near the periportal areas. (24) To expand our findings from the above BDL model, we examined H19RNA in DDC-fed mouse liver. Similarly, H19RNA did not overlap but was in close proximity to CK19 + cells ( Fig.…”

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

“…PBC and PSC are complex diseases with multiple pathogenic mechanisms activated . To evaluate the influence of the cholestatic component in Areg expression, we used two models of cholestatic liver injury of extra‐ or intrahepatic origin, BDL, and ANIT administration, respectively . Areg mRNA was strongly up‐regulated and AREG protein was detected in cholangiocytes and hepatocytes at 5 days post‐BDL, which corresponds to the peak of hepatic regenerative response (Fig.…”