Research published in Heliyon has outlined the effects of F-Klb, a signaling molecule receptor that is released under metabolic stress, on the hearts of diabetic patients.
A protector that loses its effectiveness
Fibroblast growth factor 21 (FGF21) is a regulator of metabolism that is produced both by adipose (fat) cells and the liver. Under normal circumstances, FGF21 has protective qualities: it is released in response to injury (such as heart attacks), reducing their severity [1]. Mice born without FGF21 have enlarged and less functional hearts [2].
However, in the context of metabolic issues such as diabetes, increased levels of FGF21 are associated with disease, and FGF21 is already used as a diagnostic biomarker [3]. This is not due to any negative effects of FGF21; instead, it appears to be due to a lack of its receptor, fibroblast growth receptor 1 (FGFR1), along with beta-Klotho (β-KL) [4]. The authors note that this represents a situation of resistance, in which other cells send FGF21 to a declining FGFR1-β-KL (F-Klb) pathway, and this situation appears to be a cause of cardiac problems.
These researchers delved deeper into the F-Klb pathway, determining its relationship to diabetes and its relationship to inflammation and blood vessel formation in the heart.
The F-Klb pathway in humans, mice, and cells
In samples taken from human volunteers, the expression of FGFR1 was found to be significantly decreased in diabetics, and their expression of β-KL was nearly nonexistent. These results were further explained by the murine examination, in which mice were fed a high-fat, high-sugar diet to induce diabetes. In these mice, FGF21 and its receptors were increased after eight weeks, but levels significantly dropped after 24 weeks of this diet. Like in people, the expression of β-KL was the most severely diminished.
An examination of genetically modified human vein endothelial cells (HUVECs) yielded similar results. HUVECs that expressed more F-Klb than controls, in the presence of recombinant FGF21, showed more rapid cellular migration and evidence of increased wound healing abilities. According to the researchers, these results reflect an increase in angiogenesis, the ability to form new blood vessels.
The effects of excess F-Klb on macrophages were also beneficial. In a high-fat, high-glucose medium, macrophages naturally have a more inflammatory phenotype. However, macrophages that express more F-Klb did not move towards this phenotype in the way that their unmodified counterparts did. These results suggest that F-Klb is effective against metabolic stress.
Finally, the researchers conducted a proteomic analysis based on both murine and human results. This in-depth examination revealed that, in cells that express more F-Klb, pro-inflammatory factors are downregulated and anti-inflammatory factors are upregulated. Interestingly, these positive results were recapitulated in the mice fed the high-fat, high-sugar diet for 12 weeks; it was only after long-term stress that F-Klb expression declined in these animals.
Conclusion
F-Klb clearly has value in diagnostics, and it may represent a useful tool for therapeutics. In the diagnostic arena, the F-Klb pathway and its components appear to be strong biomarkers of the progression of diabetes and associated heart disease. While upregulating F-Klb has demonstrated results in cellular cultures and animal models, more research needs to be done to determine if it is a druggable target.
Literature
[1] Liu, S. Q., Roberts, D., Kharitonenkov, A., Zhang, B., Hanson, S. M., Li, Y. C., … & Wu, Y. H. (2013). Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Scientific reports, 3(1), 2767.
[2] Planavila, A., Redondo, I., Hondares, E., Vinciguerra, M., Munts, C., Iglesias, R., … & Villarroya, F. (2013). Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nature communications, 4(1), 2019.
[3] Tanajak, P., Chattipakorn, S. C., & Chattipakorn, N. (2015). Effects of fibroblast growth factor 21 on the heart. J Endocrinol, 227(2), R13-30.
[4] Markan, K. R. (2018). Defining “FGF21 Resistance” during obesity: Controversy, criteria and unresolved questions. F1000Research, 7.
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