Fibroblast growth factor 21 is a hepatokine involved in MASLD progression

Area of Science:

• Hepatology
• Metabolic Diseases
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern.
• Fibroblast Growth Factor 21 (FGF21) plays a role in metabolic regulation.
• Understanding FGF21's role in MASLD is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of FGF21 in MASLD across multiple biological scales.
• To analyze FGF21 gene and protein expression in human MASLD samples and animal models.
• To examine the association of FGF21 genetic variants with MASLD severity.

Main Methods:

• Gene expression analysis (qPCR, RNA-Seq) on human MASLD liver samples.
• Measurement of circulating FGF21 levels in patient serum.
• Genotyping of the FGF21 rs838133 variant in MASLD cohorts.
• In vitro studies using hepatocyte cell lines exposed to free fatty acids (FFAs).
• In vivo studies using a mouse model (CDA-HFD) of steatohepatitis.

Main Results:

• Significant upregulation of FGF21 mRNA in MASLD livers compared to controls.
• Increased circulating FGF21 levels in patients with steatohepatitis versus bland steatosis.
• FGF21 overexpression in hepatocytes exposed to FFAs and in mice on a CDA-HFD diet.
• The FGF21 rs838133 A-allele was associated with increased risk of steatohepatitis and fibrosis.

Conclusions:

• Hepatic and circulating FGF21 expression are elevated in MASLD, particularly in steatohepatitis.
• FGF21 plays a significant role in the pathogenesis of MASLD.
• The FGF21 rs838133 variant is a potential biomarker for MASLD severity and progression.