Mouse Models for Hepatic Stellate Cell Activation and Liver Fibrosis Initiation

Abstract

Liver fibrosis is a severe health problem worldwide with increasing incidence. However, specific drugs for treatment of hepatic fibrosis are currently not available. Accordingly, there is a strong need to conduct intensive basic research, which also includes the necessity to use animal models to evaluate new anti-fibrotic therapy concepts. Numerous mouse models of liver fibrogenesis have been described. This involves chemical, nutritional, surgical, and genetic mouse models, which involve also activation of hepatic stellate cells (HSCs). However, for many investigators, it may be challenging to identify the most suitable model for a specific question on liver fibrosis research. In this chapter, we will provide a brief overview about the most common mouse models of HSC activation and liver fibrogenesis and thereafter provide detailed step-by-step protocols of two selected mouse fibrosis models based on own experience, which in our opinion are best suited to cover many current scientific issues. On the one hand, there is the classical carbon tetrachloride (CCl₄) model; this model of toxic liver fibrogenesis is still one of the best suited and most reproducible models for basic features of hepatic fibrogenesis. On the other hand, we also introduce the novel DUAL model of alcohol plus metabolic/alcoholic fatty liver disease developed in our laboratory, which mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis and related liver fibrosis. We describe all the information required for proper preparation and detailed implementation of both models including animal welfare aspects, thereby serving as a useful laboratory guide for mouse experimentation in liver fibrosis research.

Keywords: Alcohol; Carbon tetrachloride; Hepatic fibrosis; Hepatotoxin; Liver damage.