FGF21 as a Potential Mediator of Ultra-Processed Food-Associated Metabolic Dysfunction-Associated Steatotic Liver...

Background and Purpose: Ultra-processed food (UPF) intake is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) development, and fibroblast growth factor 21 (FGF21) is a key regulator of hepatic lipid metabolism, but its role in this association remains unclear. We aimed to investigate whether FGF21 mediates the UPF-MASLD relationship in a population-based cohort and whether berry extract (BE) protects against UPF-related liver injury through FGF21 signaling. Methods: This study included 29,386 participants with magnetic resonance imaging (MRI)-derived proton density fat fraction (PDFF) and iron-corrected T1 (cT1) from the UK Biobank. UPF intake was classified according to the NOVA system. Log-binomial and generalized linear regression models were used to estimate the associations of UPF with MASLD, PDFF, and cT1, respectively. In vivo, nine-month-old male C57BL/6J mice were fed a baked Western diet (BWD) with bilberry extract (BE, 200 mg/kg/day) or vehicle for 16 weeks. In vitro, the role of FGF21 was examined by knockdown experiments in AML12 hepatocytes. Results: UPF consumption was linearly associated with a higher risk of MASLD, with per 10% increment associated with 9% higher risk of MASLD (RR 1.09 [95% CI 1.07-1.10]), as well as dose-dependent increases in PDFF and cT1. Among the 283 plasma proteins associated with PDFF, FGF21 showed the strongest association with UPF intake and accounted for the largest proportion of mediation in the UPF-PDFF association. A significant interaction between UPF and berry intake was observed in MASLD risk (p for interaction = 0.018). In the animal model, BE supplementation for 16 weeks alleviated BWD-induced hepatic steatosis, inflammation, and glucose intolerance, while upregulating hepatic FGF21, FGFR1c, and β-Klotho expression and improving mitochondrial function. FGF21 knockdown abrogated BE's protective effect against lipid accumulation in vitro. Conclusions: FGF21 emerged as a potential mediator of the association between UPF consumption and liver fat accumulation. Anthocyanin-rich dietary interventions may offer a promising strategy to prevent MASLD progression.