Abstract
Fibroblast growth factor 21 (FGF21) is a liver‐derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype‐ and context‐dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.
Highlights
Fibroblast growth factor 21 (FGF21) a liverderived hormone that regulates interactions between energy metabolism and stress responses.[1]
To confirm the observation that FGF21 levels are elevated in patients with metabolic associated fatty liver disease (MAFLD),[14,15] we assessed its serum levels by enzyme-linked immunosorbent assay (ELISA) in 410 subjects, including 200 with biopsy-proven MAFLD and 210 healthy controls
To investigate if the receptors are activated with FGF21 that issues from either the G or A allele, we assessed for FGF21 signaling in both A and G stably expressing cell lines by measuring the FGF21 downstream signaling proteins pERK and pAKT and the expression of Egr1 and cFos, as recommended as the criteria for defining the term “FGF21 resistance."[37] As shown in Figure S7, Supporting Information, we did not observe any differences between A and G stably expressing cell lines. This data suggests that despite genotype dependent increases in FGF21 protein production, there is no alteration in FGF21 responsiveness (FGFRs and KLB) in liver or adipose tissue or in FGF21 activity
Summary
Fibroblast growth factor 21 (FGF21) a liverderived hormone that regulates interactions between energy metabolism and stress responses.[1].
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