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Published on: May 13, 2016
FGF21 deletion mildly exacerbates hepatic dysfunction in GAN diet and alcohol fed rats
Peter Aldiss1,2,3, Malte Hasle Nielsen4, Hayley Burm5
1Nottingham Digestive Diseases Centre, Translational Medical Sciences, and the Biodiscovery Institute, University of Nottingham, Nottingham, NG7 2RD, UK. peter.aldiss1@nottingham.ac.uk.
Abstract:
Fibroblast growth factor 21 (FGF21) analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease. The aim of this study was to characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human disease. We generated an FGF21 KO rat model and exposed 6-month-old WT and KO rats to either chow (n = 8 per genotype) or the obesogenic GAN (Gubra Amylin NASH) diet (n = 16 per genotype) for 12 weeks. Lack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 KO had no impact on body weight, glycaemic traits, or MASH histological endpoints, including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration, fibrosis stage, or the liver transcriptome. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats.
Insights
Fibroblast growth factor 21 (FGF21) knockout rats showed increased liver damage markers when fed an obesogenic diet. This study validates a new animal model for metabolic liver disease research.
Area of Science:
- Metabolic disease research
- Animal modeling for human diseases
- Liver disease research
Background:
- Fibroblast growth factor 21 (FGF21) analogues are being developed for metabolic and alcohol-associated liver disease.
- A validated animal model is crucial for studying human liver diseases.
Purpose of the Study:
- To characterize the first FGF21 knockout (KO) rat line.
- To validate its utility as a translational animal model for human liver diseases.
Main Methods:
- Generated an FGF21 KO rat model.
- Exposed wild-type (WT) and KO rats to either chow or an obesogenic Gubra Amylin NASH (GAN) diet for 12 weeks.
- Assessed liver parameters, body weight, glycaemic traits, and MASH histological endpoints.
Main Results:
- FGF21 KO rats fed the GAN diet exhibited increased plasma transaminases, liver weight, and liver triglycerides.
- FGF21 KO did not affect body weight, glycaemic traits, or MASH histological features.
- Endogenous FGF21 was found not to regulate drinking behavior in rats.
Conclusions:
- The FGF21 KO rat is a valuable translational model for studying metabolic liver disease.
- Endogenous FGF21 plays a role in mitigating diet-induced liver injury.
- FGF21 does not influence drinking behavior in rats.
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