Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease such as simple steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis and fibrosis. However, the molecular pathogenesis and genetic variations causing NAFLD are poorly understood. The high prevalence and incidence of NAFLD suggests that genetic variations on a large number of genes might be involved in NAFLD. To identify genetic variants causing inherited liver disease, we used zebrafish as a model system for a large-scale mutant screen, and adopted a whole genome sequencing approach for rapid identification of mutated genes found in our screen. Here, we report on a forward genetic screen of ENU mutagenized zebrafish. From 250 F2 lines of ENU mutagenized zebrafish during post-developmental stages (5 to 8 days post fertilization), we identified 19 unique mutant zebrafish lines displaying visual evidence of hepatomegaly and/or steatosis with no developmental defects. Histological analysis of mutants revealed several specific phenotypes, including common steatosis, micro/macrovesicular steatosis, hepatomegaly, ballooning, and acute hepatocellular necrosis. This work has identified multiple post-developmental mutants and establishes zebrafish as a novel animal model for post-developmental inherited liver disease.
Highlights
In order to study mechanisms of inherited liver disease progression, and to develop effective treatments for individuals with different mutations, it is essential to have appropriate models
This liver screening project was performed as a joint project with a brain laterality mutant screen, which was done at 3 dpf
Despite several thousands of mutants having been identified using forward genetic screening during development, less than 20 mutants with liver defects have been uncovered to date but mostly involved in liver specification during development [1]
Summary
In order to study mechanisms of inherited liver disease progression, and to develop effective treatments for individuals with different mutations, it is essential to have appropriate models. Forward and reverse genetic screens in zebrafish have proven to be powerful in the study of developmental defects. Studies done focusing on metabolic disorders, including inherited liver diseases, have largely not been performed. Many genes and signaling pathways controlling metabolic pathways and liver disease in mammals are highly conserved in zebrafish [1,2], though, again, few known metabolic mutants have been discovered from forward genetic. Zebrafish Models of Inherited Liver Disease nih.gov/); Metabolic Technologies, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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