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

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2021 Jun 18

PMID 34141520

Citations 11

Authors

Ali Bayoumi

Asmaa Elsayed

Shuanglin Han

Salvatore Petta

Leon A Adams

Rocio Aller

Anis Khan

Carmelo Garcia-Monzon

Maria Teresa Arias-Loste

Luca Miele

Olivier Latchoumanin

Shafi Alenizi

Rocio Gallego-Duran

Janett Fischer

Thomas Berg

Antonio Craxi

Mayada Metwally

Liang Qiao

Christopher Liddle

Hannele Yki-Jarvinen

Elisabetta Bugianesi

Manuel Romero-Gomez

Jacob George

Mohammed Eslam

Affiliations

Soon will be listed here.

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.

Citing Articles

Fibroblast growth factor 21: update on genetics and molecular biology.

Barros D, Hegele R Curr Opin Lipidol. 2024; .

PMID: 39450972 PMC: 11888835. DOI: 10.1097/MOL.0000000000000960.

A literature review of genetics and epigenetics of HCV-related hepatocellular carcinoma: translational impact.

Pan Z, Seto W, Liu C, Mao Y, Alqahtani S, Eslam M Hepatobiliary Surg Nutr. 2024; 13(4):650-661.

PMID: 39175720 PMC: 11336528. DOI: 10.21037/hbsn-23-562.

The crosstalk between fibroblast growth factor 21 (FGF21) system and substance use.

Wang T, Tyler R, Ilaka O, Cooper D, Farokhnia M, Leggio L iScience. 2024; 27(7):110389.

PMID: 39055947 PMC: 11269927. DOI: 10.1016/j.isci.2024.110389.

Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.

Gallego-Duran R, Ampuero J, Maya-Miles D, Pastor-Ramirez H, Montero-Vallejo R, Rivera-Esteban J United European Gastroenterol J. 2024; 12(8):1056-1068.

PMID: 38894596 PMC: 11485537. DOI: 10.1002/ueg2.12534.

Exportin 4 DNA promoter methylation in liver fibrosis.

Pan Z, Bayoumi A, Metwally M, George J, Eslam M PLoS One. 2024; 19(5):e0302786.

PMID: 38722973 PMC: 11081319. DOI: 10.1371/journal.pone.0302786.

References

Beck-Nielsen H, Henriksen J, Vaag A, Hother-Nielsen O . Pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Res Clin Pract. 1995; 28 Suppl:S13-25. DOI: 10.1016/0168-8227(95)01082-o. View

Li J, Biggin M . Gene expression. Statistics requantitates the central dogma. Science. 2015; 347(6226):1066-7. DOI: 10.1126/science.aaa8332. View

Halder B, Malakar A, Chakraborty S . Nucleotide composition determines the role of translational efficiency in human genes. Bioinformation. 2017; 13(2):46-53. PMC: 5463619. DOI: 10.6026/97320630013046. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Kazankov K, Barrera F, Moller H, Rosso C, Bugianesi E, David E . The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 2016; 36(10):1549-57. DOI: 10.1111/liv.13150. View

Markan K . Defining "FGF21 Resistance" during obesity: Controversy, criteria and unresolved questions. F1000Res. 2018; 7:289. PMC: 6020717. DOI: 10.12688/f1000research.14117.1. View

Schaap F, Kremer A, Lamers W, Jansen P, Gaemers I . Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie. 2012; 95(4):692-9. DOI: 10.1016/j.biochi.2012.10.019. View

Chavez A, Molina-Carrion M, Abdul-Ghani M, Folli F, DeFronzo R, Tripathy D . Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care. 2009; 32(8):1542-6. PMC: 2713625. DOI: 10.2337/dc09-0684. View

Kliewer S, Mangelsdorf D . A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21. Cell Metab. 2019; 29(2):246-253. PMC: 6368396. DOI: 10.1016/j.cmet.2019.01.004. View

10.

Tanaka T, Ngwa J, van Rooij F, Zillikens M, Wojczynski M, Frazier-Wood A . Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr. 2013; 97(6):1395-402. PMC: 3652928. DOI: 10.3945/ajcn.112.052183. View

11.

Puri P, Mirshahi F, Cheung O, Natarajan R, Maher J, Kellum J . Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2007; 134(2):568-76. DOI: 10.1053/j.gastro.2007.10.039. View

12.

Tanajak P, Pongkan W, Chattipakorn S, Chattipakorn N . Increased plasma FGF21 level as an early biomarker for insulin resistance and metabolic disturbance in obese insulin-resistant rats. Diab Vasc Dis Res. 2018; 15(3):263-269. DOI: 10.1177/1479164118757152. View

13.

Fisher F, Chui P, Nasser I, Popov Y, Cunniff J, Lundasen T . Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology. 2014; 147(5):1073-83.e6. PMC: 4570569. DOI: 10.1053/j.gastro.2014.07.044. View

14.

Chu A, Workalemahu T, Paynter N, Rose L, Giulianini F, Tanaka T . Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet. 2013; 22(9):1895-902. PMC: 3612009. DOI: 10.1093/hmg/ddt032. View

15.

Battle A, Khan Z, Wang S, Mitrano A, Ford M, Pritchard J . Genomic variation. Impact of regulatory variation from RNA to protein. Science. 2015; 347(6222):664-7. PMC: 4507520. DOI: 10.1126/science.1260793. View

16.

Dushay J, Chui P, Gopalakrishnan G, Varela-Rey M, Crawley M, Fisher F . Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010; 139(2):456-63. PMC: 4862867. DOI: 10.1053/j.gastro.2010.04.054. View

17.

Athey J, Alexaki A, Osipova E, Rostovtsev A, Santana-Quintero L, Katneni U . A new and updated resource for codon usage tables. BMC Bioinformatics. 2017; 18(1):391. PMC: 5581930. DOI: 10.1186/s12859-017-1793-7. View

18.

Lorenz R, Bernhart S, Honer Zu Siederdissen C, Tafer H, Flamm C, Stadler P . ViennaRNA Package 2.0. Algorithms Mol Biol. 2011; 6:26. PMC: 3319429. DOI: 10.1186/1748-7188-6-26. View

19.

Tanajak P . Letter to the Editor: Parameters, Characteristics, and Criteria for Defining the Term "FGF21 Resistance". Endocrinology. 2017; 158(5):1523-1524. DOI: 10.1210/en.2017-00056. View

20.

Eslam M, George J . Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol. 2019; 17(1):40-52. DOI: 10.1038/s41575-019-0212-0. View