Fibroblast growth factor 21 is a hepatokine involved in MASLD progression

Aim We aimed to assess the role of FGF21 in metabolic dysfunction‐associated steatotic liver disease (MASLD) at a multi‐scale level. Methods We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte‐derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high‐fat and choline‐deficient diet (CDA‐HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. Results A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA‐Seq (3.5 fold; FDR: 0.006; p