Fibroblast growth factor 21

Last updated

FGF21
FGF21.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FGF21 , fibroblast growth factor 21
External IDs OMIM: 609436 MGI: 1861377 HomoloGene: 10428 GeneCards: FGF21
Orthologs
SpeciesHumanMouse
Entrez

26291

56636

Ensembl

ENSG00000105550

ENSMUSG00000030827

UniProt

Q9NSA1

Q9JJN1

RefSeq (mRNA)

NM_019113

NM_020013

RefSeq (protein)

NP_061986

NP_064397

Location (UCSC) Chr 19: 48.76 – 48.76 Mb Chr 7: 45.26 – 45.26 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Fibroblast growth factor 21 is a protein that in mammals is encoded by the FGF21 gene. [5] [6] The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho. [7]

Contents

FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. [6] FGFs act through a family of four FGF receptors. Binding is complicated and requires both interaction of the FGF molecule with an FGF receptor and binding to heparin through a heparin binding domain. Endocrine FGFs lack a heparin binding domain and thus can be released into the circulation.

FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that regulates simple sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlates with reduced dopamine neurotransmission within the nucleus accumbens. [8] [9] [10]

A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant (frequency 44.7%) – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice. [11] [12] [13]

Regulation

Mechanism for FGF21-mediated regulation of metabolism FGF21 lrg.jpg
Mechanism for FGF21-mediated regulation of metabolism

FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism. [14] HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria. [15]

While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice. [16] In liver FGF21 expression is regulated by PPARα [17] and levels rise substantially with both fasting and consumption of ketogenic diets.

Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter. [18]

Function

FGF21 stimulates glucose uptake in adipocytes but not in other cell types. [19] This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. [19] Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion. [20]

β-Klotho ( KLB ) functions as a cofactor essential for FGF21 activity. [21]

In cows plasma FGF21 was nearly undetectable in late pregnancy (LP), peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation (EL). Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT. [22]

Clinical significance

Serum FGF-21 levels were significantly increased in patients with type 2 diabetes mellitus (T2DM) which may indicate a role in the pathogenesis of T2DM. [23] Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease [24] and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state. [25]

A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant (frequency 44.7%) – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice. [11] [12] [13]

Animal studies

Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. [26]

FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism. [27]

In mice FGF21 is strongly induced in liver by prolonged fasting via PPAR-alpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response. FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state. [28] FGF21 is induced in both rodents and humans consuming a low protein diet. [29] [30] FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acids methionine [31] [32] or threonine, [33] or with reduced levels of branched-chain amino acids. [34]

Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC-1α-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1α and histone 3. [35]

Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking. Chronically, the rise in FGF21 expression in the liver may protect against liver damage. [7]

Related Research Articles

<span class="mw-page-title-main">Brown adipose tissue</span> Type of adipose tissue

Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

<span class="mw-page-title-main">Klotho (biology)</span> Human enzyme

Klotho is an enzyme that in humans is encoded by the KL gene. The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21. When the subfamily is not specified, the word "klotho" typically refers to the α-klotho subfamily, because α-klotho was discovered before the other members.

Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.

<span class="mw-page-title-main">Fibroblast growth factor 23</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the FGF23 gene. FGF23 decreases reabsorption of phosphate in the kidney. Mutations in FGF23 can lead to its increased activity, resulting in autosomal dominant hypophosphatemic rickets.

<span class="mw-page-title-main">Farnesoid X receptor</span> Protein-coding gene in the species Homo sapiens

The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4, is a nuclear receptor that is encoded by the NR1H4 gene in humans.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">PPARGC1A</span> Protein

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.

<span class="mw-page-title-main">Liver X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.

<span class="mw-page-title-main">Estrogen-related receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

<span class="mw-page-title-main">FGF18</span> Mammalian protein found in Homo sapiens

Fibroblast growth factor 18 (FGF18) is a protein that is encoded by the Fgf18 gene in humans. The protein was first discovered in 1998, when two newly-identified murine genes Fgf17 and Fgf18 were described and confirmed as being closely related by sequence homology to Fgf8. The three proteins were eventually grouped into the FGF8 subfamily, which contains several of the endocrine FGF superfamily members FGF8, FGF17, and FGF18. Subsequent studies identified FGF18's role in promoting chondrogenesis, and an apparent specific activity for the generation of the hyaline cartilage in articular joints.

<span class="mw-page-title-main">FGF19</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders.

<span class="mw-page-title-main">3-Aminoisobutyric acid</span> Chemical compound

3-Aminoisobutyric acid is a product formed by the catabolism of thymine.

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.

<span class="mw-page-title-main">Jeffrey Flier</span> American physician

JeffreyFlier is an American physician, endocrinologist; widely cited scientist; the Higginson Professor of Medicine and Physiology at Harvard Medical School; and a Distinguished Service Professor at the same institution. He was the 21st Dean of the Faculty of Medicine at Harvard University from 2007 to 2016.

Fibroblast growth factor 15 is a protein in mouse encoded by the Fgf15 gene. It is a member of the fibroblast growth factor (FGF) family but, like FGF19, FGF21 and FGF23, has endocrine functions. FGF19 is the orthologous protein in humans. They are often referred together as FGF15/19.

FGF15/19 refers to two orthologous fibroblast growth factors which share 50% aminoacid identity and have similar functions. FGF15 was described in the mouse; FGF19 was found in humans and other species. They share physiological functions and so are often referred to as FGF15/19 or as FGF15/FGF19.

Eleftheria Maratos-Flier is an American endocrinologist, and emerita Professor of Medicine at Harvard Medical School, best known for her expertise in the pathophysiology and prevention of obesity-related metabolic disorders, and for her discoveries on the neuroendocrine control of feeding behaviour. She is a contributing author to known textbooks and reviews in internal medicine, endocrinology, and physiology. Her marriage with professor Jeffrey Flier, was noted by Forbes as a lasting and productive bond between eminent medical scholars. They have two adult daughters who are also physicians. She is also known as Terry Maratos-Flier.

Hepatokines are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.

<span class="mw-page-title-main">Alexei Kharitonenkov</span> Russian biochemist

Alexei Kharitonenkov is a Russian-American researcher best known for his discoveries of endocrine functions of Fibroblast Growth Factor 21 (FGF21) and its prospects in developing novel therapies for metabolic diseases. He is also known for his landmark identification of the Signal-Regulatory family of proteins (SIRPs), (SIRPs), and their corresponding protein-tyrosine phosphatases, which helped unveil the molecular machinery of immune self-recognition and their potential for the development of drugs to fight cancer.

References

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  14. ↑ Vilà-Brau A, De Sousa-Coelho AL, Mayordomo C, Haro D, Marrero PF (June 2011). "Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line". The Journal of Biological Chemistry. 286 (23): 20423–30. doi: 10.1074/jbc.M111.235044 . PMC   3121469 . PMID   21502324.
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  33. ↑ Yap, Yann W.; Rusu, Patricia M.; Chan, Andrea Y.; Fam, Barbara C.; Jungmann, Andreas; Solon-Biet, Samantha M.; Barlow, Christopher K.; Creek, Darren J.; Huang, Cheng; Schittenhelm, Ralf B.; Morgan, Bruce (June 9, 2020). "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution". Nature Communications. 11 (1): 2894. Bibcode:2020NatCo..11.2894Y. doi:10.1038/s41467-020-16568-z. ISSN   2041-1723. PMC   7283339 . PMID   32518324.
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Further reading

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