Exploring Endocrine FGFs - Structures, Functions and Biomedical Applications

Overview

Journal Int J Biochem Mol Biol

Specialty Biochemistry

Date 2024 Sep 23

PMID 39309613

Authors

Phuc Phan

Gajotane Ternier

Oshadi Edirisinghe

Thallapuranam Krishnaswamy Suresh Kumar

Affiliations

Soon will be listed here.

Abstract

The family of fibroblast growth factors (FGFs) consists of 22 members with diverse biological functions in cells, from cellular development to metabolism. The family can be further categorized into three subgroups based on their three modes of action. FGF19, FGF21, and FGF23 are endocrine FGFs that act in a hormone-like/endocrine manner to regulate various metabolic activities. However, all three members of the endocrine family require both FGF receptors (FGFRs) and klotho co-receptors to elicit their functions. α-klotho and β-klotho act as scaffolds to bring endocrine FGFs closer to their receptors (FGFRs) to form active complexes. Numerous novel studies about metabolic FGFs' structures, mechanisms, and physiological insights have been published to further understand the complex molecular interactions and physiological activities of endocrine FGFs. Herein, we aim to review the structures, physiological functions, binding mechanisms to cognate receptors, and novel biomedical applications of endocrine FGFs in recent years.

Citing Articles

Overexpression and biophysical and functional characterization of a recombinant FGF21.

Phan P, Hoang J, Kumar T Biophys Rep (N Y). 2025; 5(1):100198.

PMID: 39884432 PMC: 11869967. DOI: 10.1016/j.bpr.2025.100198.

New insights into FGF21 alleviates diabetic cardiomyopathy by suppressing ferroptosis: a commentary.

Chen K, Wang S Cardiovasc Diabetol. 2024; 23(1):424.

PMID: 39593068 PMC: 11590201. DOI: 10.1186/s12933-024-02519-1.

References

Gerhard G, Styer A, Wood G, Roesch S, Petrick A, Gabrielsen J . A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013; 36(7):1859-64. PMC: 3687273. DOI: 10.2337/dc12-2255. View

Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H . Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor?. PLoS One. 2011; 6(8):e22976. PMC: 3148241. DOI: 10.1371/journal.pone.0022976. View

Rabadi S, Udo I, Leaf D, Waikar S, Christov M . Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol. 2017; 314(1):F132-F139. PMC: 5866351. DOI: 10.1152/ajprenal.00081.2017. View

Camilleri M, Nord S, Burton D, Oduyebo I, Zhang Y, Chen J . Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea. Aliment Pharmacol Ther. 2020; 52(5):808-820. DOI: 10.1111/apt.15967. View

Tiong K, Tan B, Choo H, Chung F, Hii L, Tan S . Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival. Oncotarget. 2016; 7(36):57633-57650. PMC: 5295378. DOI: 10.18632/oncotarget.9328. View

Flamme I, Ellinghaus P, Urrego D, Kruger T . FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One. 2017; 12(10):e0186979. PMC: 5658123. DOI: 10.1371/journal.pone.0186979. View

Yang C, Jin C, Li X, Wang F, McKeehan W, Luo Y . Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One. 2012; 7(3):e33870. PMC: 3307775. DOI: 10.1371/journal.pone.0033870. View

Ornitz D, Itoh N . Fibroblast growth factors. Genome Biol. 2001; 2(3):REVIEWS3005. PMC: 138918. DOI: 10.1186/gb-2001-2-3-reviews3005. View

Imel E, Glorieux F, Whyte M, Munns C, Ward L, Nilsson O . Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019; 393(10189):2416-2427. PMC: 7179969. DOI: 10.1016/S0140-6736(19)30654-3. View

10.

Hanson K, Fisher K, Hooper N . Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction. Neuronal Signal. 2021; 5(2):NS20200101. PMC: 8204227. DOI: 10.1042/NS20200101. View

11.

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

12.

Hill C, Laeger T, Albarado D, McDougal D, Berthoud H, Munzberg H . Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. Sci Rep. 2017; 7(1):8209. PMC: 5557875. DOI: 10.1038/s41598-017-07498-w. View

13.

Muise E, Azzolina B, Kuo D, El-Sherbeini M, Tan Y, Yuan X . Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol. 2008; 74(2):403-12. DOI: 10.1124/mol.108.044826. View

14.

Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R . FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2009; 285(8):5165-70. PMC: 2820743. DOI: 10.1074/jbc.M109.068783. View

15.

Kurosu H, Choi M, Ogawa Y, Dickson A, Goetz R, Eliseenkova A . Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007; 282(37):26687-26695. PMC: 2496965. DOI: 10.1074/jbc.M704165200. View

16.

Deng Z, Deng S, Zhang M, Tang M . Fibroblast Growth Factors in Depression. Front Pharmacol. 2019; 10:60. PMC: 6370647. DOI: 10.3389/fphar.2019.00060. View

17.

Itoh N, Ohta H, Konishi M . Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy. Front Endocrinol (Lausanne). 2015; 6:154. PMC: 4586497. DOI: 10.3389/fendo.2015.00154. View

18.

Abu-Odeh M, Zhang Y, Reilly S, Ebadat N, Keinan O, Valentine J . FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes. Cell Rep. 2021; 35(13):109331. PMC: 8293281. DOI: 10.1016/j.celrep.2021.109331. View

19.

Liu Y, Cao M, Cai Y, Li X, Zhao C, Cui R . Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression. Front Cell Dev Biol. 2020; 8:95. PMC: 7044267. DOI: 10.3389/fcell.2020.00095. View

20.

Goetz R, Mohammadi M . Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol. 2013; 14(3):166-80. PMC: 3695728. DOI: 10.1038/nrm3528. View