Aldiss Peter, Nielsen Malte Hasle, Burm Hayley, Oró Denise, Hansen Henrik H, Feigh Michael, Gillum Matthew P
Nottingham Digestive Diseases Centre, Translational Medical Sciences, and the Biodiscovery Institute, University of Nottingham, Nottingham, NG7 2RD, UK.
National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, and University of Nottingham, Nottingham, UK.
NPJ Metab Health Dis. 2025 May 28;3(1):21. doi: 10.1038/s44324-025-00062-5.
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.
成纤维细胞生长因子21（FGF21）类似物正处于临床开发阶段，用于治疗代谢性和酒精相关性肝病。本研究的目的是对首个FGF21基因敲除（KO）大鼠品系进行表征，以验证其作为重现人类疾病的转化动物模型的效用。我们构建了一个FGF21 KO大鼠模型，并将6月龄的野生型（WT）和KO大鼠分别给予普通饲料（每种基因型n = 8）或致肥胖的GAN（Gubra Amylin NASH）饲料（每种基因型n = 16），持续12周。在喂食GAN的FGF21 KO大鼠中，内源性FGF21的缺失会增加血浆转氨酶、肝脏重量和肝脏甘油三酯的总水平。FGF21 KO对体重、血糖特征或MASH组织学终点没有影响，包括肝脂肪变性、NAS评分、小叶炎症、气球样变性、纤维化阶段或肝脏转录组。最后，我们证明内源性FGF21并不调节大鼠的饮酒行为。
