Fibroblast growth factor 21 and its novel association with oxidative stress

Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine-member of the FGF family. It is synthesized mainly in the liver, but it is also expressed in adipose tissue, skeletal muscle, and many other organs. It has a key role in glucose and lipid metabolism, as well as in energy balance. FGF21 concentration in plasma is increased in patients with obesity, insulin resistance, and metabolic syndrome. Recent findings suggest that such increment protects tissue from an increased oxidative stress environment. Different types of physical stress, such as strenuous exercising, lactation, diabetic nephropathy, cardiovascular disease, and critical illnesses, also increase FGF21 circulating concentration. FGF21 is now considered a stress-responsive hormone in humans. The discovery of an essential response element in the FGF21 gene, for the activating transcription factor 4 (ATF4), involved in the regulation of oxidative stress, and its relation with genes such as NRF2, TBP-2, UCP3, SOD2, ERK, and p38, places FGF21 as a key regulator of the oxidative stress cell response. Its role in chronic diseases and its involvement in the treatment and follow-up of these diseases has been recently the target of new studies. The diminished oxidative stress through FGF21 pathways observed with anti-diabetic therapy is another clue of the new insights of this hormone.

Keywords: Diabetes; FGF21; Insulin resistance; Metabolic syndrome; Oxidative stress.

Fig. 1

Conditions associated with an increased FGF21 expression. FGF21 increases in four main circumstances: a) Mitochondrial diseases; b) oxidative stress, c) physical stress situations, such as ketogenic diets, free fatty acids release, lactation, treatment with exogenous growth hormone, and moderate to vigorous exercising; d) pathological physical stress such as obesity, anorexia nervosa, skeletal muscle autophagy deficiency, critical illness, hypothermia, amino acid deprivation, undernutrition, and diabetic nephropathy.

Fig. 2

FGF21 and its association with oxidative stress. Metabolic diseases, such as obesity, hyperglycemia, insulin resistance, dyslipidemia, and metabolic syndrome are in both-ways involved with the presence of endoplasmic reticulum stress and oxidative stress. Oxidative stress leads to inflammation responses that result in apoptosis and other pathologies like cardiovascular diseases and cancer. FGF21 inhibits inflammation in response to oxidative stress.

Fig. 3

Activation of FGF21 by the endoplasmic reticulum stress. Three pathways are induced by ER (Endoplasmic reticulum) stress: 1) the activating transcription factor 6 (ATF6), 2) the inositol-requiring enzyme 1 (IRE1), and 3) the protein kinase-like endoplasmic reticulum kinase (PERK). ATF6 increases the expression of chaperones and foldases promoting the degradation of unfolded proteins. IRE1 increases ER folding capacity by detecting misfolded ER proteins and inducing the site-specific splicing of X-box-binding protein 1(XBP1). XBP1 activation up-regulates genes that improve clearance of unfolded proteins and enhance cell survival and binds the endoplasmic reticulum stress element (ERSE) to enhance the expression of FGF21. The PERK activation leads to the phosphorylation of serine-51 (Ser-51) of eukaryotic initiation factor 2 alpha (EIF2 alpha), a transcription factor that catalyzes the first step in the beginning of protein synthesis, in order to decrease the ER load. Furthermore, EIF2 alpha phosphorylation prompts simultaneous induction of ATF4 (activating transcription factor 4), which initiates the expression of its target gene, transcription factor C/EBP homologous protein (CHOP). Three antioxidant mechanisms are activated when FGF21 is expressed due to ER stress: 1) UCP3 (uncoupling protein 3) and the SOD2 (superoxide dismutase-2), decreasing the action of ROS (reactive oxygen species). 2) ERK (extracellular signal-regulated kinase) induces the activation of CREB (cAMP responsive element binding protein) repressing NFkappaB that works as a pro-inflammatory factor, and 3) MAPK (mitogen-activated protein kinase) and p38 that activate AMPK (adenosine monophosphate kinase), decreasing the apoptosis. Finally, oxidative stress is diminished.