FGF21

Official Full Name

fibroblast growth factor 21

Organism

Homo sapiens

GeneID

26291

Background

Theis gene encodes a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. This protein is a secreted endocrine factor that functions as a major metabolic regulator. The encoded protein stimulates the uptake of glucose in adipose tissue. [provided by RefSeq, Mar 2016]

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Detailed Information

Human fibroblast growth factor composited by 22 family members responsible for cell differentiation, proliferation and metabolism. As one of FGF family members, it belonged to endocrine FGF subgroup with FGF19 and FGF23. The biological activity of FGF21 working as a metabolism regulation factor has been firstly reported by Nishimura. It can promote glucose uptake of mouse 3T3-L1 adipocytes and human primary adipocytes by stimulating glucose transporter 1 gene expression. Subsequent research further confirmed that liver cell expressed FGF21 protein can significantly elevate sensitivity to insulin and shown good efficacy for blood sugar lowering and insulin sensitization. Recombinant FGF21 protein can significantly lower body weight, blood sugar and triglycerides to normal levels, thus enhancing insulin resistance and alleviating fatty liver disease in type 2 diabetes non-human primate animal model. The regulation of FGF21 on the body metabolic balance initiates by sensing nutritional status in biological state. Upregulation of FGF21 in blood induced by activating the nuclear receptor peroxisome proliferation activator receptor alpha (PPARα) signaling pathway can promote transformation of fatty acids released from the liver into ketones. In addition, activation of hypothalamus-pituitary-adrenal axis by FGF21 would accelerate corticosterone release and gluconeogenesis, thereby maintaining glucose homeostasis. Traditional FGF family members play its role by binding to FGF receptor (FGFR) with tyrosine kinase activity in cell membrane, while absence of heparin binding site make FGF21 as an endocrine factor to exert its biological effects via secretion from organ into blood. Combination of FGF21 N-terminal with FGFR upon binding in its C-terminal between a transmembrane protein called β-kloth form a stable FGF21/β-klotho/FGFR complex, which would activate downstream related molecular signals to complete its biological effect.

Fgf-21 Work as A Biomarker for NAFLD and Liver Injury

Although multiple protective works in metabolism of FGF21 have been found according to previous study, there is a significant elevation of FGF21 circulating levels in NAFLD patients and obesity induced fatty liver mice model.

Regulation of Fgf-21 on Liver Metabolism

Liver work as both endocrine and targeting organ for FGF21, early research revealed that loss of FGF21 gene can significantly increase body weight after ketogenic feeding and exacerbate steatosis by injuring ketogenic synthesis. Recent study found that recombinant FGF21 protein can inhibit the activity of mammalian target protein complex of rapamycin1 and increase hepatic insulin sensitivity. Activation of receptor γ coactivator-1α by FGF21 induced peroxisome proliferation would promote liver fatty acid oxidation.

Fig 1. Schematic summary of the pathophysiology of nonalcoholic steatohepatitis (NASH) (Manuel et al. 2020)

References:

A NISHIMURA T, NAKATAKE Y, KONISHI M. (2000) 'Identification of a novel FGF, FGF-21, preferentially expressed in the liver, Biochim Biophys Acta, 2000, 1492(1): 203-206. DOI: 10.1016/s0167-4781(00) 00067-1.
gong q, hu z, zhang f. (2016) 'Fibroblast Growth Factor 21 Improves Hepatic Insulin Sensitivity by Inhibiting Mammalian Tar- Get of Rapamycin Complex 1 in mice, Hepatology, 2016, 64 (2): 425-438. DOI: 10. 1002/hep. 28523.
Mohammad Zarei, Javier Pizarro-Delgado, Emma Barroso. (2020) 'Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis, Trends in Pharmacological Sciences, doi: 10.1016/j.tips.2019.12.005.

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