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FLASH GENE
Symbol FGF21 contributors: mct/pgu - updated : 05-05-2018
HGNC name fibroblast growth factor 21
HGNC id 3678
Location 19q13.33      Physical location : 49.259.343 - 49.261.582
DNA
TYPE functioning gene
STRUCTURE 2.24 kb     3 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site   HRE
text structure
  • ROR response element was identified in the proximal promoter of the FGF21 gene and shown to exhibit functional activity
  • three circadian-responsive elements, including an E-box, a ROR-response element site
  • a functional D-box element in the FGF21 promoter region (NFIL3 directly binds to this site within the promoter region of the FGF21 gene and suppresses its transcription)
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 940 19.4 209 - 2005 15902306
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart     Homo sapiens
    Digestiveliver   highly Homo sapiens
    Endocrinepancreas     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadiposebrown   Homo sapiens
    Connectiveadiposewhite   Homo sapiens
    Muscularstriatumskeletal highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    not specificadipocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES Hydrophobic
    STRUCTURE
    motifs/domains
  • hydrophobic N terminus (signal sequence), critical for fibroblast growth factor receptor (FGFR) activation
  • lack of the FGF heparin-binding domain
  • a typical 120 AAs â-trefoil core structure like the traditional FGFs
  • C-terminus critical for binding to KLB
    • HOMOLOGY
    interspecies ortholog to murine Fgf21
    intraspecies paralog to FGF19
    Homologene
    FAMILY
  • fibroblast growth factor family of secreted mitogen
  • FGF19 subfamily
  • heparin-binding growth factor family
    • CATEGORY secretory , signaling cytokine growth factor
    SUBCELLULAR LOCALIZATION extracellular
    basic FUNCTION
  • stimulating glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1
  • directly affects the endocrine function of the pancreas by enhancing insulin production and beta cell survival and reduces the maladaptive glucagon release
  • with FGF19 share the ability to regulate glucose, lipid, and energy homeostasis
  • attenuates hormone-stimulated lipolysis in adipocytes
  • functions as an endocrine hormone and is produced in peripheral tissues such as liver, white/brown adipose, pancreas, and skeletal muscle
  • significantly reduced the expression of the lipid droplet-associated phosphoprotein perilipin without affecting differentiation
  • is an insulin-regulated myokine
  • hepatic hormone that regulates peripheral glucose tolerance, torpor, and hepatic lipid metabolism
  • role as a key regulator of hepatic lipid metabolism
  • having only metabolic effects
  • potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake (
  • stimulates glucose uptake in an insulin-independent manner, possibly by up-regulating the SLC2A1 expression
  • FGF21 and GH1 are metabolic hormones that play important roles in regulating glucose and lipid metabolism
  • might be involved in regulating futile energy cycling by way of the glycerol/fatty acid cycle
  • liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders
  • enhances glucose uptake by transcriptional activation of the SLC2A1 gene
  • FGF21-induced SLC2A1 expression is mediated by KLB-ERK1/2-ELK1/SRF signaling cascade, which in turn transactivates the SLC2A1 gene through a highly conserved cis-element within its promoter
  • acts in an autocrine fashion in adipocytes and is required to mediate effects of the PPARG agonist class of antidiabetic drugs
  • circulating hepatokine that beneficially affects carbohydrate and lipid metabolism
  • FGF19 and FGF21 can regulate glucose, lipid, and energy metabolism, while FGF23 regulates phosphate homeostasis
  • important role of FGF21 and CNPY2 in the regulation of LDLRs
  • increases the stability of LDLRs in cells
  • FGF21 and statin increase LDLR levels and lipid uptake in an additive manner
  • acts on adipose tissue to promote lipolysis and responses to fasting
  • modulates glucose and lipid metabolism during fasting
  • may also inhibit bone growth by directly suppressing chondrogenesis and GH action at the growth plate
  • important role of FGF21 in the regulation of lipid metabolism during amino acid starvation
  • FGF21 released by cardiomyocytes protects cardiac cells against hypertrophic insults
  • hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth
  • defines an important liver-neuroendocrine axis that modulates female reproduction in response to nutritional challenge
  • inhibits growth plate chondrogenesis and longitudinal bone growth during undernutrition both systemically and locally in the growth plate
  • might be involved in the mechanisms of metabolic improvement of several anti-diabetic agents
  • play an important role during fasting and starvation by stimulating gluconeogenesis in the liver and inducing lipolysis in white adipose tissues
  • FGF19, FGF21 and FGF23 are circulating hormones that regulate critical metabolic processes in a variety of tissues, and FGF21 stimulates insulin sensitivity, energy expenditure and weight loss
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
  • an FGF21-NR1I2 signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in Nonalcoholic fatty liver disease (NAFLD)
  • FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction
    • a component
    INTERACTION
    DNA
    RNA
    small molecule cofactor,
  • requires a specific cofactor for its binding to a certain type of FGF21 receptor and subsequent activation of FGF21 signaling pathways
    • protein
  • binds directly to KLB through its C-terminus
  • target of PPARG
  • link between RORA, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose
    • and lipid homeostasis
  • link between FGF21 and a key circadian output protein, NFIL3
    • and FGF21 is a direct target of NFIL3
  • key mediator of the physiologic and pharmacologic actions of PPARG
  • the effect of FGF21 depended on the presence of CNPY2 and involved a down-regulation in MYLIP level
  • both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB
  • FGF21 effects on chondrocyte function are specific and depend on the normal activity of the FGFR1 and MAPK3
  • by binding FGFR1 and/or FGFR3, FGF21 prevents GH-mediated stimulation of chondrocyte proliferation and differentiation
  • is essential for FGF21 activity and KLB in adipose tissue contributes to the beneficial metabolic actions of FGF21
  • EHMT2 mediates NFIL3-dependent suppression of hepatic FGF21 by enhancing histone methylation (H3K9me2) of the FGF21 promoter
  • GCG controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways
  • FGF21 prevents the GH effects on chondrocytes by activating LEPROT and LEPROTL1
  • specifically and directly modulate LEPROT/LEPROTL1 expression and function in chondrocytes
  • exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21
  • DNM2 dependent endocytosis of FGFR1 is required for angiogenesis in response to FGF2 and the non-classical FGF ligand, FGF21
  • is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (DDIT3)
  • sustained activation of MTOR signaling in skeletal muscle regulated whole-body metabolism through the induction of FGF21, which, over the long term, caused severe lipodystrophy
  • BHBLHE40 is a novel negative regulator of hepatic FGF21 expression
  • MAP3K4 acts as a critical node to integrate FGF20-FGFR1 signaling responses to specifically influence hair cells (HCs) development
  • NR1D1 is a specific modulator of FGF21 signaling in adipose tissue
  • KLB is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans
  • ANGPTL6-mediated increase in PPARA expression resulted in increased FGF21 expression, thereby promoting beta-oxidation
  • chenodeoxycholic acid (CDCA) regulation of FGF21 transcription is mediated at least partially by an EIF2A-dependent increase in ATF4 expression
  • KLB serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling
  • KLB is an obligate coreceptor, mediating both fibroblast growth factor FGF19 and FGF21 signaling
    • cell & other
    REGULATION
    induced by PPRGA in response to physiological conditions requiring increased fatty acid oxidation
    by HMGCS2 activity or by the inclusion of the oxidized form of ketone bodies (acetoacetate)
    metformin which induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK
    mitochondrial stress and functions as a ‘mitokine’
    repressed by NFIL3 (strongly suppresses FGF21 transcription by binding to a D-box element in the distal promoter region)
    Other regulated by KLB (its expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion)
    synergistic interaction between glucagon and insulin in the regulation of FGF21 secretion and FGF21 mRNA abundance
    regulated by endoplasmic reticulum (ER) stress, a condition that is observed in a number of diseases including non-alcoholic fatty liver disease (NAFLD)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in diabetic subjects after metformin therapy
    constitutional     --over  
    in hypertension, atherosclerosis and coronary artery disease
    constitutional     --over  
    during chronic undernutrition inhibits GH action on chondrocytes by activating LEPROT and LEPROTL1
    constitutional     --over  
    during chronic food restriction is associated with reduced bone growth and growth hormone (GH) insensitivity
    constitutional     --over  
    may directly suppress growth plate chondrocyte proliferation and differentiation
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • serum FGF21 can be potentially used as a biomarker for nonalcoholic fatty liver disease
  • sensitive biomarker of mitochondrial disease
    • Therapy target
    SystemTypeDisorderPubmed
    diabetemetabolic syndrom 
    attractive therapeutic agent to treat type 2 diabetes and the associated metabolic syndrome
    diabete  
    administration of FGF21 can be beneficial in treating hyperglycemia and insulin resistance
    diabetetype 2 
    FGF19 may serve as an ideal complement for FGF21 in diabetes therapy development
    ANIMAL & CELL MODELS
  • fgf21(-/-) mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development