成纤维细胞生长因子21 （FGF21）和FGF15/FGF19 属于同一亚组 FGF，并被认为在治疗2型糖尿病以及相关的代谢功能障碍和病理性疾病方面具有治疗潜力。已经提出 FGF19 可通过FGF受体4（FGFR4）介导在FVB小鼠（以其对好友白血病病毒B的敏感性而命名）中诱导细胞增生和肝肿瘤。这项工作的目的是调查FGF21是否也可能通过肝特异性Fgfr4基因敲除（KO）小鼠介导促进增殖。我们进行了一个机械性的7天研究，包括女性Fgfr4 fl/fl 和Fgfr4 KO小鼠，分别进行每日皮下注射FGF21或FGF19 （阳性对照）两次。采用半自动生物成像分析评估Ki-67肝脏标记指数。结果显示，FGF21和FGF19处理的Fgfr4 fl/fl小鼠显著增加。有趣的是，在Fgfr4 KO小鼠中，这种效果在FGF19和FGF21两种处理中均不存在，这表明FGFR4受体不仅在介导 FGF19 引导最终导致肝肿瘤的肝细胞增生过程中至关重要，而且FGFR4/FGF21信号也对肝细胞增殖活性产生影响，但根据当前的知识，这不会促进肝细胞肝癌的形成。

Fibroblast growth factor 21 (FGF21) and FGF15/FGF19 belong to the same subgroup of FGFs and are believed to have therapeutic potential in the treatment of type 2 diabetes and associated metabolic dysfunctionalities and pathological conditions. FGF19 has been proposed to induce hyperplasia and liver tumors in FVB mice (named after its susceptibility to Friend leukemia virus B), mediated by the FGF receptor 4 (FGFR4). The goal of this work was to investigate whether FGF21 might also have a potential proliferative effect mediated via FGFR4 using liver-specific Fgfr4 knockout (KO) mice. We conducted a mechanistic 7-day study involving female Fgfr4 fl/fl and Fgfr4 KO mice with a treatment regimen of twice daily or daily subcutaneous injections of FGF21 or FGF19 (positive control), respectively. The Ki-67 liver labeling index (LI) was evaluated by a semi-automated bioimaging analysis. The results showed a statistically significant increase in FGF21- and FGF19-treated Fgfr4 fl/fl mice. Interestingly, in Fgfr4 KO mice, this effect was absent following both treatments of FGF19 and FGF21, indicating that not only the FGFR4 receptor is pivotal for the mediation of hepatocellular proliferation by FGF19 leading finally to liver tumors but it seems also that FGFR4/FGF21 signaling has an impact on the hepatocellular proliferative activity, which does not promote the formation of hepatocellular liver tumors based on the current knowledge.