Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus

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.

Biomarkers of Metabolic (Dysfunction)-associated Fatty Liver Disease: An Update

“… 6 , 8 Multiple variants have been determined to be implicated in MAFLD susceptibility and progression, which are involved in the regulation of key pathways, such as those involved in lipid metabolism, insulin signaling, immune cell activation, adipocytokine and myokine activities, oxidative stress and inflammation responses. 6 , 42 – 48 This has been the subject of other recent reviews. 6 , 8 , 49 …”

“…6,8 Multiple variants have been determined to be implicated in MAFLD susceptibility and progression, which are involved in the regulation of key pathways, such as those involved in lipid metabolism, insulin signaling, immune cell activation, adipocytokine and myokine activities, oxidative stress and inflammation responses. 6,[42][43][44][45][46][47][48] This has been the subject of other recent reviews. 6,8,49 Despite the initial optimism that genetic discoveries would demonstrate immediate utility as diagnostic biomarkers, none of the discovered genetic variants for complex diseases such as MAFLD, including major genetic determinants such as of PNPLA3 and TM6SF2 (even with their observed relatively high effect sizes), can now be used as biomarkers for diagnostic clinical implementation.…”

Translation Reprogramming as a Novel Therapeutic Target in MAFLD

“…Synonymous variant in the fibroblast growth factor 21 (FGF21) can for instance drive the development of hepatic inflammation in a patient with MAFLD. [31] 2.2.1. tRNA Abundance tRNAs represent 10-15% of the total RNA in a cell with >500 human tRNA genes known and are vital molecules for translation, acting as nexus molecules between mRNAs and proteins and representing an additional layer of regulation of translation and protein synthesis. The composition of the tRNA pool is dynamic and can vary substantially in response to environmental cues or disease.…”

“…Synonymous variant in the fibroblast growth factor 21 (FGF21) can for instance drive the development of hepatic inflammation in a patient with MAFLD. [ 31 ]…”

Paracrine Fibroblast Growth Factor-Based Therapy: An Unexpected Panacea for Metabolic-Dysfunction-Associated Fatty Liver Disease (MAFLD)

“…4 The FGF21 metabolic axis plays a multifaceted role in controlling homeostasis of lipid, glucose, and energy metabolism. 5,6 At the same time, both FGF19 and FGF21 are closely related to the progression of liver fibrosis. 7 FGF19 analogs (such as NGM-282 8 ) and FGF21 analogs (such as PF-05231023, 9,10 BMS-986036, 11 LY2405319, 12 and AKR-001 13 ) are undergoing evaluation in clinical trials or nearing clinical trials around the world.…”