Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 63
  • Home
  • Print this page
  • Email this page
Cover page of the Journal of Health Sciences


 
 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 2  |  Page : 68-85

Molecular description of fibroblast growth factor and mechanisms by which fibroblast growth factor-21 mediating biological actions and acting as a biologic biomarker of cardiovascular diseases


1 Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia
2 Department of Medical Laboratory Sciences, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia

Date of Submission21-Mar-2020
Date of Acceptance22-Apr-2020
Date of Web Publication23-Jun-2020

Correspondence Address:
Dr. Leta Shiferaw Melaku
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia. E-mail:
Ethiopia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_92_20

Rights and Permissions
  Abstract 


Fibroblast growth factor (FGF) family members are mostly secreted as signaling proteins with diverse functions in development and metabolism. FGFs can be classified as intracellular, paracrine, and endocrine FGFs by their action mechanisms. FGF-21 is a novel member of endocrine FGF subfamily with pleotropic actions. Recent findings indicate that FGF-21 can act as a cardiomyokine; that is, it is produced by cardiac cells and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF-21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key coreceptor known to confer specific responsiveness to FGF-21 action. It has been shown to exert cardioprotective effects in against cardiac hypertrophy, myocardial infarction, cardiac inflammation, cardiac ischemia-reperfusion injury, diabetic cardiomyopathy, and oxidative stress. It also promotes energy supply to the heart through fatty acid β-oxidation. Intracellular mechanisms involving peroxisome proliferator-activated receptor α and sirtunin 1 mediate transcriptional regulation of the FGF-21 gene in response to exogenous stimuli. This review explores the molecular mechanism by which FGF-21 provides cardioprotection.

Keywords: Fibroblast growth factor, fibroblast growth factor-21, heart


How to cite this article:
Melaku LS, Debela N. Molecular description of fibroblast growth factor and mechanisms by which fibroblast growth factor-21 mediating biological actions and acting as a biologic biomarker of cardiovascular diseases. Indian J Health Sci Biomed Res 2020;13:68-85

How to cite this URL:
Melaku LS, Debela N. Molecular description of fibroblast growth factor and mechanisms by which fibroblast growth factor-21 mediating biological actions and acting as a biologic biomarker of cardiovascular diseases. Indian J Health Sci Biomed Res [serial online] 2020 [cited 2020 Sep 29];13:68-85. Available from: http://www.ijournalhs.org/text.asp?2020/13/2/68/287425




  Introduction Top


Cell–cell communication with secreted signaling molecules ensures proper development and metabolism. Most fibroblast growth factors (FGFs) are well-established secreted signaling proteins of ~150–300 amino acids that play critical roles in development and metabolism.[1] The human/mouse FGF family comprises 22 members that can be classified as intracellular, paracrine, and endocrine FGFs by their action mechanisms [Figure 1].[2],[3] They can also be divided into seven subfamilies based on phylogeny and sequence.[4],[5],[6] In another word, the paracrine FGFs are further divided into five subfamilies, whereas the autocrine and endocrine FGFs are composed of one subfamily each [Figure 1].[7],[8] The paracrine subfamilies include the FGF-1 subfamily which comprising FGF-1 and 2; the FGF-4 subfamily which comprising FGF-4, 5, and 6; the FGF-7 subfamily which comprising FGF-3, 7, 10, and 22; the FGF-9 subfamily which comprising FGF-9, 16, and 20; and the FGF-8 subfamily which comprising FGF-8, 17, and 18. The intracrine (autocrine) FGF subfamilies include the FGF-11 subfamily which comprising FGF-11, 12, 13, and 14, while the endocrine-acting FGF-19 subfamily comprises FGF-15, 19, 21, and 23.[9],[10],[11],[12],[13],[14],[15]
Figure 1: Classifications of fibroblast growth factors. Fibroblast growth factors have 22 members which can be divided into three classes and subdivided into seven subfamilies

Click here to view


FGFs share a core homology region of about 120 amino acids, consisting of 12 antiparallel β-strands arranged into three sets of four-stranded β-sheets [Figure 2].[16],[17],[18] This globular core domain is flanked by N- and C-terminal regions that are highly divergent with respect to both length and sequence among FGFs, particularly across subfamilies.[19] Moreover, even within some subfamilies, the sequence identity at the N-terminus can be rather limited. The sequence identity of the N-terminal regions of FGF-4 and 6 is only 36% compared to 69% for their core regions and that of FGF-9 and 20 is only 38% compared to 86% for their core regions.[20],[21],[22]
Figure 2: A schematic representation of fibroblast growth factor core homology regions. N- and C-termini are labeled and the 12 β-sheets that compose the β-trefoil core are indicated

Click here to view


Paracrine and endocrine FGFs, to produce their biological functions, bind extracellularly to four cell surface tyrosine kinase FGF receptors (FGFRs).[23],[24],[25],[26] The human FGFR gene family comprises four members, FGFR1–FGFR4, that encode single-pass transmembrane proteins of ~ 800 amino acids with three extracellular immunoglobulins (Igs) such as domains I, II, and III and a split intracellular tyrosine kinase domain.[19],[25],[27] FGFR1, FGFR2, and FGFR3 genes encode two alternative splicing variants (b and c) of Ig-like domain III, which is a determinant of ligand-binding specificities.[28] Thus, there are seven FGFR proteins, FGFRs 1b, 1c, 2b, 2c, 3b, 3c, and 4, with distinct ligand-binding specificity.[19],[25],[27] In structural terms, FGFRs are comprised of an extracellular ligand-binding portion consisting of three Ig-like domains (D1–D3), a single transmembrane helix, and an intracellular tyrosine kinase domain [Figure 3].[5],[29],[30],[31],[32] Structural studies have shown that ligand binding requires both D2 and D3 domains.[20],[33],[34] The D1 domain and D1–D2 linker that harbors the acid box are dispensable for ligand binding and in fact suppress FGF and heparan sulfate (HS)-binding affinity of the D2–D3 region.[35],[36] The specificity of FGFR for ligand binding is modulated by alternative splicing of mutually exclusive “b” and “c” exons in the second half of the D3 domain.[37],[38] This D3 alternative splicing event is tissue specific and elaborates the number of principal FGFRs from four to seven: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4.[37],[39] Structural studies have shown that D3 alternative splicing modulates the FGF-binding specificity/promiscuity of FGFRs by switching the primary sequence of key ligand-binding epitopes in D3.[21]
Figure 3: An overview of fibroblast growth factor receptor structural biology. A schematic of fibroblast growth factor receptor shows its three immunoglobulin-like domains. D1 and the acid box are involved in autoinhibition, the heparan sulfate-binding site is located on D2 and alternative splicing takes place in the latter half of D3. D2 and D3 are necessary and sufficient for ligand binding. An intracellular kinase domain mediates downstream signaling

Click here to view


Although FGFRs are essential for FGF action on the target cells, they cannot activate intracellular signaling without coreceptors[40] and their coreceptors are different, which determines that they have different bioactivity due to the activation of various pathways.[41],[42] A wealth of genetic studies in mice and flies as well as cell-based studies have established that all FGF signaling requires heparin (HS), albeit with differing affinities.[43],[44],[45] HS is a highly sulfated linear polymer of alternating glucuronate (GlcA) and N-acetylglucosamine (GlcNAc) monosaccharides that undergo heterogeneous deacetylation and N-sulfation on GlcNAc, O-sulfation on both GlcA and GlcNAc, and epimerization on GlcA.[46] HS impinges on FGF signaling through multiple mechanisms, including coordination/stabilization of FGF-FGFR binding and dimerization,[47] control of FGF gradients in the extracellular matrix (ECM),[48] and protection of FGFs against thermal instability and proteolytic degradation.[49],[50] The heparin-binding site (HBS) of all FGFs is located within the core region and is composed of residues from the β1–β2 loop and the segment spanning the β10–β12 strand.[51] FGFRs also interact with HS via residues from the gA helix, the gA-βA' loop, the βA'-βB loop, and the βB strand. Structural studies have shown that HS promotes the formation of a 2:2:2 FGF–FGFR–HS cell surface signaling unit in which each ligand binds both receptors in the complex and the two receptors additionally make contact with one another [Figure 4]a and [Figure 4]b.[47],[52] Two HS molecules bind in a symmetric fashion to a positively charged HS-binding cleft formed from the union of the HBS of the two FGFs and two FGFRs at the membrane-distal end of the dimer.[53],[54] By simultaneously engaging the HBS of both FGF and FGFR, HS stabilizes protein–protein contacts both within the 1:1 FGF–FGFR complex and between the two FGF–FGFR complexes in the dimer. In addition to promoting FGF–FGFR binding and dimerization, emerging data show that HS also controls the diffusion and morphogenetic gradients of paracrine FGFs in the ECM[48] and that the HS affinity of a ligand ultimately determines whether that FGF acts in a paracrine or endocrine fashion.[55] Dimerization of the extracellular domains of FGFRs juxtaposes the intracellular kinase domains, affording them with sufficient opportunity to transphosphorylate each other on the A-loop tyrosines. A-loop tyrosine phosphorylation increases the intrinsic kinase activity of FGFR kinase by stabilizing the active conformation of the kinase.[56] Activated kinases then further transphosphorylate each other on tyrosines within the C-tail, kinase insert, and juxtamembrane regions.[57],[58],[59]
Figure 4: Heparan sulfate-dependent dimerization of the fibroblast growth factor-fibroblast growth factor receptor complex. (a) A surface representation of the fibroblast growth factor-fibroblast growth factor receptor-heparin ternary complex. fibroblast growth factor is in dark gray, the D2 and D3 domains of fibroblast growth factor receptor are in light gray and heparin is represented as sticks in black. (b) The complex has been rotated ninety degrees around an axis parallel to the plane of the page to reveal heparin binding the heparin-binding site in the membrane distal cleft of the complex. (c) The boxed region from (a) is expanded to show the fibroblast growth factor residues involved in hydrogen bonding to heparan sulfate. There a total of 16 hydrogen bonds between fibroblast growth factor and heparan sulfate. For the sake of clarity, only those three hydrogen bonds mediated by backbone atoms are shown

Click here to view


The phosphorylated tyrosines in the C-tail and juxtamembrane regions of activated FGFR serve as the recruitment sites for SH2 domains of phospholipase Cγ (PLCγ)[60],[61] and CRKL,[62] respectively. In the case of PLCγ, this recruitment serves two purposes: (i) it facilitates phosphorylation of PLCγ to increase its enzymatic activity and (ii) it brings PLCγ to the vicinity of its substrate PIP2 in the plasma membrane. Hydrolysis of PIP2 generates two second messengers: inositol triphosphate (IP3) and diacylglycerol (DAG) that stimulate Ca2+ release from intracellular stores and protein kinase C (PKC) activation, respectively.[63],[64],[65] In contrast, CRKL is an adaptor protein that lacks intrinsic enzymatic activity. Recruitment of CRKL to the phosphorylated tyrosine in the juxtamembrane region of FGFR1 and FGFR2 leads to the translocation of associated Rac1/Cdc42 to the plasma membrane, which culminates in cytoskeletal reorganization and cell motility.[62] Finally, activated FGFR phosphorylates FGFR substrate 2α (FRS2α),[66] another adaptor protein that, unlike PLCγ and CRKL, associates constitutively (independently of receptor phosphorylation) with the juxtamembrane region of FGFR.[67],[68],[69] Phosphorylation of FRS2α by the activated FGFR generates docking sites for the SH2 domains of the adaptor protein growth factor receptor-bound 2 (GRB2)[66] and the phosphatase SHP2,[70] leading to the activation of the RAS-mitogen-activation protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT pathways [Figure 4]c.[71]

Multiple studies show that HS proteoglycans, which extracellularly localize at neighboring cells as cofactors for FGFRs, are essential coreceptors for paracrine and autocrine FGFs.[25],[42] Binding to HS proteoglycans is essential for FGF signaling in a paracrine manner.[28] In contrast, endocrine FGFs with reduced HS-binding affinity are unable to function in a paracrine manner.[1] Endocrine FGFs require α-Klotho or β-Klotho as a cofactor for FGFRs to mediate their attachment and activation of target FGFRs.[7],[27] However, endocrine FGFs cannot efficiently bind to FGFR, α-Klotho or β-Klotho alone; they efficiently bind to the FGFR–Klotho complex. α-Klotho and β-Klotho, which share structural similarities and characteristics with each other, are single-pass transmembrane proteins of ~ 1000 amino acids with a short cytoplasmic domain.[72] The binding site for the FGFR–Klotho complex is localized in the C-terminal tail of endocrine FGF.[73] FGF-19 activates FGFR4 with β-Klotho and FGF-21 activates FGFR1c with β-Klotho, whereas FGF-23 activates FGFR1c with α-Klotho.[28] FGF-19 and FGF-23 exhibit metabolic and proliferative activities. However, FGF-21 is a unique FGF with metabolic activity, but no proliferative activity.[74] The functional dimerization and transphosphorylation of FGFRs induced by FGF binding result in the activation of FGFRs, followed by the activation four key intracellular signaling pathways: RAS/RAF/MAPK, PI3K/serine–threonine protein kinase AKT, signal transducer and activator of transcription (STAT), and phosphoinositide PLCγ [Figure 5].[7],[28],[75]
Figure 5: The four key intracellular signaling pathways activated by fibroblast growth factor-fibroblast growth factor receptors

Click here to view



  Intracellular Signal Transduction Top


FGF binding activates the FGFR tyrosine kinase by inducing receptor dimerization and transautophosphorylation of the kinase domain [Figure 6]a.[27] For FGFR1, six tyrosine residues are sequentially phosphorylated to fully activate the kinase domain [Figure 6]b.[58],[76] In the first phase of activation, Y653 is phosphorylated, resulting in a 50–100-fold increase in tyrosine kinase activity.
Figure 6: Fibroblast growth factor signaling pathways. (a) Binding of canonical fibroblast growth factors to fibroblast growth factor receptor with herapan sulfate (or HSPG) as a cofactor induces the formation of ternary fibroblast growth factor-fibroblast growth factor receptor-herapan sulfate complex, which activates the fibroblast growth factor receptor intracellular tyrosine kinase domain by the phosphorylation of specific tyrosine residues. The activated receptor is coupled to intracellular signaling pathways including the RAS-mitogen-activation protein kinase, phosphatidylinositol 3-kinase-AKT, phospholipase Cγ, and signal transducer and activator of transcription pathways. The RAS-mitogen-activation protein kinase pathway: The major fibroblast growth factor receptor kinase substrate, fibroblast growth factor receptor substrate 2α, which is constitutively associated with the juxtamembrane region of fibroblast growth factor receptor (peptide: MAVHKLAKSIPLRRQVTVSADS), interacts with CRKL bound to pY463 and is phosphorylated by the activated fibroblast growth factor receptor kinase. Phosphorylated fibroblast growth factor receptor substrate 2α recruits the adaptor protein growth factor receptor-bound 2, which then recruits the guanine nucleotide exchange factor SOS. The recruited SOS activates the RAS GTPase, which then activates the mitogen-activation protein kinase pathway. Mitogen-activation protein kinase activates members of the E26 transformation-specific transcription factor family such as Etv4 (Pea3) and Etv5 (Erm) and negative regulators of the fibroblast growth factor receptor signaling pathways such as SHP2, CBL, Sprouty, similar expression to fibroblast growth factor , and dual-specificity phosphatase 6. The phosphatidylinositol 3-AKT pathway: The recruited growth factor receptor-bound 2 also recruits the adaptor protein GAB1, which then activates the enzyme phosphatidylinositol 3-kinase, which then phosphorylates the enzyme AKT. AKT has multiple activities including activation of the mammalian target of rapamycin complex 1 through inhibition of tuberous sclerosis complex 2 and phosphorylation of the FOXO1 transcription factor causing it to exit the nucleus. The phospholipase Cγ pathway: activated fibroblast growth factor receptor kinase recruits and activates the enzyme phospholipase Cγ, which produces inositol triphosphate and diacylglycerol by the hydrolysis of PIP2. Inositol triphosphate induces calcium ion release from intracellular stores and the activation of downstream signaling pathways. Diacylglycerol activates the enzyme protein kinase C and its downstream signaling pathways. Growth factor receptor-bound 14 inhibits activation of phospholipase Cγ. The signal transducer and activator of transcription pathway: fibroblast growth factor receptor kinase also activates signal transducer and activator of transcription 1, 3, and 5. Signal transducer and activator of transcription 3 interacts with phosphorylated tyrosine 677 (pYxxQ motif). These activated signaling pathways mostly regulate gene expression in the nucleus. Sprouty interacts with growth factor receptor-bound 2 to inhibit the RAS-mitogen-activation protein kinase pathway and to regulate the phosphatidylinositol 3-kinase-AKT pathway. Growth factor receptor-bound 2 dimers are docked at the c-terminus of fibroblast growth factor receptor 2 where they inhibit SHP2, allowing low-level receptor kinase activity. Molecules shaded red generally function to inhibit fibroblast growth factor receptor signaling. (b) Dimerization of the fibroblast growth factor receptor 1 kinase domain leads to sequential phosphorylation of tyrosine residues (1P–6P), leading to increasing activity of the fibroblast growth factor receptor kinase and phosphorylation of tyrosine substrates for CRKL, signal transducer and activator of transcription, growth factor receptor-bound 14, and phospholipase Cγ binding. In the first phase of activation, Y653 (1P), in the activation loop, is phosphorylated, resulting in a 50- to 100-fold increase in kinase activity. In the third phase of activation, Y654 (6P), in the activation loop, is phosphorylated, resulting in an overall 500–1000 fold increase in kinase activity. Y730 is weakly phosphorylated. Phosphorylation of Y677 allows docking of signal transducer and activator of transcription 3 and phosphorylation of Y766 allows docking of either growth factor receptor-bound 14 or phospholipase Cγ. Ligand-induced receptor activation phosphorylates growth factor receptor-bound 2, leading to its dissociation from the receptor. Tyrosine residues correspond to human fibroblast growth factor receptor 1 (accession NP_075598). (c) Binding of endocrine fibroblast growth factor to fibroblast growth factor receptor with Klotho as a cofactor induces the formation of ternary fibroblast growth factor-fibroblast growth factor receptor-Klotho complex, which leads to activation of the fibroblast growth factor receptor tyrosine kinase. (d) Fibroblast growth factor receptor ligand 1 is a protein containing three extracellular immunoglobulin-like domains with similarity to fibroblast growth factor receptors. Fibroblast growth factor receptor ligand 1 has a single transmembrane domain, and a short intracellular tail with no tyrosine kinase domain. The short cytoplasmic domain contains an SH2 binding motif that interacts with SHP1. Fibroblast growth factor receptor ligand 1 is not simply a decoy receptor, but rather a nontyrosine kinase signaling molecule

Click here to view


In the second phase of activation, Y583, and then Y463, Y766, and Y585 are phosphorylated. In the third phase of activation, Y654 is phosphorylated, resulting in a further 10-fold (overall 500–1000-fold) increase in tyrosine kinase activity. Phosphorylation of two additional tyrosine residues, 677 and 766, is required, respectively, for STAT3 and PLCγ binding.[61],[77],[78] The adaptor protein, FRS2α is constitutively docked to its binding site in the juxtamembrane region of FGFRs and anchored to the cell membrane through myristoylation [Figure 6]b.[66],[68],[79] The activated FGFR phosphorylates adaptor proteins for four major intracellular signaling pathways: RAS-MAPK, PI3K-AKT, PLCγ, and STAT [Figure 6]a and [Figure 6]b.[25],[61],[80],[81],[82] Activation of the RAS-MAPK and PI3K-AKT pathway is initiated by the phosphorylation of FRS2α. FRS2α phosphorylation and extracellular signal-regulated kinase (ERK) 1/2 activation are partially dependent on the phosphorylation of Y463 and the presence of CRKL.[82],[83] pY463 directly interacts with the adapter protein CRKL and with much lower affinity to the related protein, CRK.[62],[84],[85] Downstream of RAS and PI3K, FGFR signaling has been shown to regulate several distinct MAP kinases, including ERK1/2, JNK, and p38.[86],[87],[88],[89],[90] Activated (phosphorylated) FRS2α binds the membrane-anchored adaptor protein, GRB2, and the tyrosine phosphatase SHP2.[66],[70] GRB2 further activates the RAS-MAPK pathway through the recruitment of SOS and the PI3K-AKT pathway through the recruitment of GAB1 to the signaling complex [Figure 6]a.[66],[91] The RAS-MAPK pathway regulates the expression of diverse target genes through activation of E26 transformation-specific (ETS) transcription factors. Etv4 (Pea3) and Etv5 (Erm) are the ETS transcription factors that are often transcriptionally induced by FGF signaling.[92],[93],[94],[95] Phosphorylation of ETS transcription factors by activated MAPK allows interaction with DNA and regulation of target gene expression.[89] In contrast to the RAS-MAPK pathway, the PI3K-AKT pathway functions to inhibit the activity of target molecules such as the fork head box class transcription factor, FOXO1, and the cytosolic tuberous sclerosis complex 2 (TSC2). FOXO1, a pro-apoptotic effector, is inactivated by AKT phosphorylation, causing it to exit the nucleus and promote cell survival.[96] AKT also activates the mammalian target of rapamycin (mTOR) complex 1 through phosphorylation and inhibition of TSC2, ultimately stimulating cell growth and proliferation.[96] Phosphorylation of PLCγ by the activated FGFR tyrosine kinase leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce IP3 and DAG [Figure 6]a. IP3 increases intracellular calcium ion levels and DAG activates PKC.

The adaptor protein, GRB14, also interacts with the activated FGFR1 at multiple sites, including pY766[97] (and possibly pY776). Binding of GRB14 to pY766 inhibits tyrosine phosphorylation and activation of PLCγ [Figure 6]a and [Figure 6]b.[98] In addition, the SRC homology-2 protein, SHB, interacts with pY766 and acts to enhance the phosphorylation of FRS2α and the mitogenic response to FGFs in an immortalized brain endothelial cell line.[99] The activated FGFR also phosphorylates and activates STAT1, STAT3, and STAT5, to regulate STAT pathway target gene expression [Figure 6]a and [Figure 6]b.[77],[100],[101],[102],[103] STAT1 was activated in the chondrocytes derived from thanatophoric dysplasia patients with a constitutively active mutant of FGFR3,[100] and STAT1 activation in response to FGF1 in the primary growth plate chondrocytes was necessary to suppress proliferation.[104] However, using a rat chondrosarcoma cell line that stops growing in response to FGF1, it has been controversial as to whether STAT1 or MAPK signaling mediates the observed growth arrest.[104],[105] In cancer cells, under conditions of gene amplification or overexpression of FGFR3, STAT3 was phosphorylated resulting in the activation of downstream target genes.[77] In brain microvascular endothelial cells, FGF signaling was found to activate STAT5, which was necessary for migration, invasion, and tube formation.[106] However, activation of downstream signaling pathways is thought to be qualitatively similar to FGFR1 and FGFR2 and different from FGFR3 and FGFR4.[62],[82],[107] Similarities and differences in signaling of the four FGFRs could be mediated by differential rates of endocytosis,[108] by differential subcellular trafficking after ligand activation,[109],[110] or by differences in the affinity or specificity for adaptor proteins that couple to downstream signaling cascades.[71] Inhibitor of FGFR signaling Sprouty (SPRY) is an intracellular negative regulator of receptor tyrosine kinases, including FGFR, vascular-endothelial growth factor receptor, platelet-derived growth factor receptor, and nerve growth factor receptor.[111],[112] The human/mouse SPRY family is composed of four members, SPRY1–SPRY4. Most SPRY genes are ubiquitously expressed in both embryos and adult tissues. In FGF signaling, SPRY interacts with GRB2 to inhibit the RAS-MAPK pathway and to regulate the PI3K-AKT pathway [Figure 6]a.[113],[114] The phenotypes of SPRY-knockout (KO) mice indicate that SPRYs are essential for development and growth. The deregulation of SPRY function often results in human cancers and autoimmune diseases.[111],[112] Similar expression to FGF (SEF) is a transmembrane protein that functions as an antagonist of FGF signaling through the RAS-MAPK pathway [Figure 6]a.[115],[116]

SEF functions by binding to activated MEK to inhibit dissociation of the MEK–MAPK (ERK1/2) complex, thus blocking nuclear translocation of activated MAPK.[114],[117] The extracellular domain of SEF may also interact directly with the FGFR to inhibit receptor phosphorylation.[118] Dual-specificity phosphatase 6 (Dusp6) encodes an ERK-specific MAPK phosphatase.[119] Dusp6 expression is transcriptionally upregulated by FGFR signaling and Dusp6 expression patterns closely resemble those of FGFs.[120],[121],[122],[123] Dusp6 servesin vivo as a negative feedback regulator of FGFR signaling by directly dephosphorylating MAPK (ERK1 and ERK2) on phosphotyrosine and phosphothreonine residues [Figure 6]a.[119] CBL, an E3 ubiquitin ligase, forms a ternary complex with phosphorylated FRS2α and GRB2, resulting in the ubiquitination and degradation of FGFR and FRS2 in response to FGF stimulation.[124] FGFR2 activation can also increase CBL–PI3K interactions, leading to PI3K degradation and attenuated signaling.[125] SHP2 binds to phosphorylated FRS2 following ligand activation of the FGFR.[18] SHP2 functions to dephosphorylate FGFR2 and GRB2 [Figure 6]a. However, activation of SHP2 (by phosphorylation) and access to the FGFR are also inhibited by receptor-bound GRB2 [Figure 6]a, [Figure 6]b, [Figure 6]c, [Figure 6]d.[126],[127]


  Physiological Roles of Fibroblast Growth Factor-21 in Health and Human Disease Top


FGF-21 is a novel member of endocrine FGF subfamily that consists of 209 amino acids residues[3] and encoded by the FGF-21 gene located in chromosome 19 in human[128],[129] and chromosome 7 in mice.[9],[130],[131] FGF-21 expression is mainly regulated by peroxisome proliferator-activated receptor α (PPARα)[132],[133],[134] and PPARγ [Figure 6].[135],[136] Even though FGF-21 is preferentially expressed within a liver,[128] in other tissues, such as pancreas,[137] white[135],[136],[137],[138],[139],[140],[141] adipose tissues (WAT) and brown[142] adipose tissues (BAT), skeletal muscle,[143],[144] and heart[128],[137],[145],[146],[147] also expressed. FGF-21 activity depends on its binding to FGFRs and a cofactor called β-Klotho, a single-pass transmembrane protein that is predominantly expressed in metabolic organs, including liver, WAT, and pancreas.[148],[149],[150] This cofactor is crucial for the FGF-21 specificity of the target cells increasing the ability of FGFRs to bind FGF-21.[42],[151] To activate FGF-21 signaling, FGF-21 binds to FGFR1c and FGFR2c with its C-terminus and also with β-Klotho as its coreceptor with its N-terminus, to form the FGFR/β-Klotho complex.[40],[42],[139],[152],[153] The FGFR/β-Klotho complex then stimulates the autophosphorylation of the FRS2α, which is the first step in the downstream signaling of FGF-21.[40],[42]

FGF-21 has various physiological roles in healthy condition and pharmacological role under unhealthy condition.[154],[155] Unlike the prototypical members of the FGF family, FGF-21 acts as an important regulator of energy homeostasis.[130],[132],[133],[150]

Role fibroblast growth factor-21 in energy homeostasis

During the course of starvation, there is a gradual transition of the energy source of our body from glucose and glycogen to fat, protein, and acetate.[156],[157] Glucose is an important energy source for the body, especially for the brain where β-oxidation of fatty acids is unavailable. During the first stage of fasting (several hours), glucose is supplied by glycogenolysis. Subsequently, gluconeogenesis occurs to maintain the level of glucose through various pathways, such as the pathway in which phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate, and the pathway in which glycerol kinase and glycerol 3-phosphate dehydrogenase catalyze the conversion of glycerol, a product of adipose tissue lipolysis, to dihydroxyacetone phosphate.[158] Under prolonged fasting, triglyceride (TG) is metabolized into glycerol and free fatty acids (FFAs) through β-oxidation. The FFAs are converted to ATP and acetyl-coenzyme A (CoA), which are metabolized to ketone bodies, such as acetone, acetoacetate, and β-hydroxybutyrate. Ketone bodies are used as an energy source under severe starvation because long-chain fatty acids cannot pass through the blood–brain barrier. FGF-21 reduces glycogenolysis and induces β-oxidation, ketogenesis, and gluconeogenesis even under normal feeding conditions.[133],[130] It is an important rheostat that shifts the energy source from glycogen to fat and ketone bodies for survival under energy deprivation status. Studies using mice model have revealed that FGF-21 induces lipolysis and maintains plasma glucose level by regulating the expressions of hormone-sensitive lipase (HSL) and adipose TG lipase (ATGL) in WAT and ectopic expressions of pancreatic lipases in the liver.[133] The production of glucose through gluconeogenic enzymes, such as PEPCK and glucose-6-phosphatase, is partially mediated by the transcriptional coactivator PPAR-γ coactivator-1 α (PGC1α), whose the expression is regulated by FGF-21.[130] Administration of FGF-21 to the obese rodent model was shown to suppress glucose, insulin, and TGs levels in the plasma and TGs levels in the liver and to enhance lipid usage. It has been reported that FGF-21 induces glucose transfer into the adipocytes by increasing GLUT1 expression,[9] increases the quantity of pancreatic islets and insulin secretion from each pancreatic islet,[159] and suppresses plasma glucagon levels.[9] Glucose uptake induced by FGF-21 is additive and independent of insulin.

This glucose entry into adipocytes results in its storage as TG. Moreover, the ability of FGF-21 for increasing the thermogenic capacity of WAT could, at least in part, lead to a greater clearance of glucose.[134],[160] FGF-21 might also act on glucagon metabolism and vice versa. FGF-21 suppresses hepatic glucose production, increases liver glycogen, and lowers glucagon in mice.[161] On the other hand, hepatic expression of PPARα and FGF-21 is stimulated by hepatic glucagon receptor activation in a manner that is further augmented by fatty acids.[162] It has also been reported that FGF-21 preserves β-cell function and survival by the activation of ERK1/2 and AKT signaling pathways.[159] All these actions would be associated with a reduction of blood glucose. Indeed, systemic administration of FGF-21 has shown to reduce plasma glucose to near-normal levels in genetically compromised diabetic rodents[9] and fasting plasma glucose, fructosamine, insulin, and glucagon without developing hypoglycemia in diabetic rhesus monkeys.[163],[164] FGF-21 has shown beneficial effects on lipid profile in animal models. Systemic administration of FGF-21 was also followed by a decrease in the plasma TG, FFA, and cholesterol in genetically compromised diabetic and obese rodents.[9],[164] Moreover, FGF-21 administration also induces changes in the mRNA profiles of several genes involved in lipid metabolism in diet-induced obesity mice.[165] In WAT, FGF-21 increased mRNA levels of uncoupling protein 1 (UCP1), PGC1α, HSL, and ATGL, whereas in BAT, FGF-21 administration led to an elevation of UCP1 and acetyl-CoA carboxylases 2 transcripts.[165] In diabetic rhesus monkeys, chronic FGF-21 therapy significantly improved lipid profile, including a decrease in TG and low-density lipoprotein (LDL) and an increase in high-density lipoprotein (HDL).[163] FGF-21 also seems to be involved in the regulation of body fat mass. Circulating FGF-21 concentrations are significantly elevated in obesity[153] in rodents responding poorly to exogenous FGF-21, indicating that obesity could be an FGF-21-resistant state.[166] FGF-21 increases energy expenditure in mice with free access to food, thereby correcting obesity,[164],[165] and transgenic mice overexpressing FGF-21 have shown to be resistant to diet-induced metabolic abnormalities and obesity.[9] A small but significant weight loss was also reported after chronic FGF-21 therapy in diabetic nonhuman primates.[163] These antiobesity actions of FGF-21 appear to be mediated by an increase in energy expenditure and preferential fat utilization because weight loss is accompanied by elevated oxygen consumption, increased core body temperature in the absence of decrease in total caloric intake, or effect on physical activity.[164],[165]

FGF-21 also exerts antiobesity effects through the regulation of energy expenditure in BAT by stimulating sympathetic nerve activity through a mechanism that depends on the neuropeptide corticotrophin-releasing factor.[167] During prolonged starvation, the body adapts by preserving critical survival systems, such as heartbeat and brain activity, while reducing other energy expenditures, including growth, reproduction, and maintenance of skeletal stature. FGF-21 inhibits growth hormone (GH) signaling by inhibiting the Janus kinase/STAT signaling pathway.[168] This results in suppression of insulin-like growth factor gene (Igf-1) and other GH target genes in the liver. FGF-21 also inhibits female fertility by suppressing the vasopressin–kisspeptin signaling cascade at the suprachiasmatic nucleus (SCN) in the hypothalamus, which leads to the inhibition of the proestrus surge of luteinizing hormone.[169] In addition, FGF-21 promotes bone loss.[170],[171] This is consistent with a previous report that FGF-21 induces the stimulation of the sympathetic nervous system, which is known to induce bone loss.[167] FGF-21 induces a hibernation-like state of reduced body temperature in rodents called torpor. This is induced by fasting, accompanied by increased ketogenesis, and associated with the induction of pancreatic lipases in the liver.[133],[172] FGF-21 transgenic mice show all of the above characteristics. Furthermore, transgenic overexpression of FGF-21 in mice extends their lifespan without having to reduce food intake or affecting the nicotinamide adenine dinucleotide metabolism or AMP-activated protein kinase (AMPK) and mTOR signaling.[173] It has also been reported that FGF-21 works on the SCN and dorsal vagal complex of the hindbrain to regulate circadian rhythm, which is important for the adaptive starvation response.[174] FGF-21 has also been reported to be induced in ground squirrels during hibernation, although the administration of FGF-21 did not induce hibernation in them.[175] These facts indicate that FGF-21 plays important roles in survival and longevity by maintaining energy homeostasis. Besides the induction of torpor by FGF-21 under fasting conditions to maintain the energy source, recent reports claim a link between FGF-21 and thermogenesis. Thermogenic stimulations induce mRNA expression and secretion of FGF-21 from BAT.[142],[160],[176],[177],[178] FGF-21 is reported to stimulate browning of the inguinal WAT in addition to increasing Ucp1 expression in both BAT and WAT.[141],[160],[179],[180] The correlation of FGF-21 with browning has been suggested as the mechanism by which FGF-21 improves metabolic disorders, such as obesity and type 2 diabetes.

However, two recent studies using Ucp1-null mice treated with a long-acting FGF-21 analog claim that FGF-21 does not require either UCP1 or browning of WAT to improve body weight and glucose homeostasis.[181],[182] Moreover, FGF-21 enhances the expression of genes involved in thermogenesis within brown fat increasing body temperature.[134] Further investigations would reveal more details of the role of FGF-21 in heat production.

Role of fibroblast growth factor-21 in atherosclerosis and coronary heart disease

Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima.[183] The accrued evidence indicated that lipid-lowering therapy limits the progression of atherosclerosis and reduces coronary artery disease (CAD) events.[184] Since FGF-21 plays an important role in the regulation of lipid metabolism, the effect of FGF-21 in atherosclerosis is of interest.[150] Clinical studies showed that increased circulating FGF-21 levels were discovered in atherosclerotic patients or the individuals with high risk of developing atherosclerosis.[185],[186] In addition, anin vivo study demonstrated that increased serum FGF-21 was observed in aortas of apolipoprotein E-deficient mice (apoE−/−).[187] Strong evidence identified that administration of exogenous FGF-21 significantly improved lipid metabolic disorders and reduced atherosclerotic plaque areas in these animals.[188] Moreover, Lin et al. also reported that FGF-21 deficiency enhanced atherosclerotic deterioration and mortality in apoE−/−,[187] implying that increased serum FGF-21 in patients with atherosclerosis described previously induces beneficial effect rather than the basic for atherosclerotic pathogenesis.[188] Mechanistic study indicated that FGF-21-induced prevention of atherosclerosis was associated with suppression of endoplasmic reticulum stress-mediated apoptosis in apoE−/−.[189],[190] In addition, FGF-21 100 mg/kg per day subcutaneous (sc) injections for 4 weeks could protect the abdominal aorta from arteriosclerotic lesions through lipid regulation and ER stress-induced vascular cell apoptosis in the ApoE-knockout (KO) model.[189] Further mechanistic studies revealed that the prevention of atherosclerosis by FGF-21 was attributed to the fine-tuning of multiorgan cross-talk among the liver, adipose tissue, and blood vessels, characterized by the suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice with atherosclerosis.[187] Although FGF-21 functions in an endocrine manner, whether FGF-21 can also induce a direct protection to the blood vessels remains unclear.[191] For decades, lowering levels of LDL cholesterol and increasing level of HDL have formed the cornerstone of management of patients with atherosclerotic CVD.[150]

Strong evidence demonstrated that FGF-21 dramatically improved the condition of atherosclerosis in Wistar rats by decreasing serum LDL levels and increasing serum HDL levels.[190] Moreover, FGF-21-induced antioxidative function is also involved in its therapeutic effect in atherosclerotic Wistar rat characterized by increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde.[192] Along with the development of atherosclerosis, the artery's lining becomes hardened, stiffened, and swollen with all sorts of “gunge,” including fatty deposits and abnormal inflammatory cells, to form a plaque and then eventually deteriorates into coronary heart disease (CHD).[193],[194],[195] Strong evidence indicated that cardiac endothelial cell dysfunction may be an early initiating factor for atherosclerosis which facilitates the development of CHD.[196] Oxidized LDL (ox-LDL) is a proatherogenic lipoprotein that accumulates in the vascular wall and contributes to vascular dysfunction at the early stage of atherosclerosis development.[197],[198],[199],[200],[201],[202],[203],[204],[205],[206] Enhanced serum ox-LDL and antibodies against its epitopes are predictive for endothelial dysfunction and subsequent CHD.[206] Previousin vitro study indicated that both FGF-21 mRNA and protein expressions were increased in response to ox-LDL treatment in cardiac endothelial cells, and this was protective against apoptosis caused by ox-LDL.[207] Further, FGF-21 has been reported to prevent high glucose-induced cell damage and endothelial nitric oxide synthase dysfunction through an AMPK-dependent pathway in endothelial cells.[208] Therefore, the relationship between FGF-21 and CHD is of interest. Shen et al. reported that serum FGF-21 level was positively associated with CHD in clinics.[209],[210] Another study also confirmed that serum levels of FGF-21 are increased in patients with CHD independently associated with adverse lipid profiles.[150],[185] In contrast, another study indicated that serum FGF-21 has been associated with hypertriglyceridemia, hyperinsulinemia, and pericardial fat accumulation but not associated with CHD.[211] This paradox may be explained by decreased body mass index of healthy controls compared to patients with CHDs.[150]

Role of fibroblast growth factor-21 in diabetic cardiomyopathy

Diabetic patients develop the diabetic cardiomyopathy (DCM) independent of CAD and hypertension.[212],[213] DCM is attributed to multiple pathogenic factors, including hyperglycemia, hyperlipidemia, and inflammation.[214],[215],[216]

Cardiomyopathy is a late consequence of diabetes-induced early cardiac responses, especially the myocardial apoptosis.[217],[218] Thus, treatments to reduce cardiac apoptosis may help control DCM.[150] Recently, it was reported that cardiac FGF-21 mRNA expression was positively associated with the development of diabetes in the type 1 diabetic mice, suggesting that the increased cardiac FGF-21 expression may be beneficial to the heart in this regard.[219] In this study, there was also cardiac apoptosis in early diabetic mice, which was remarkably prevented by the administration of recombinant FGF-21.[219] In another study in which mice was deficient FGF-21, FGF-21 is essential in the prevention of the progression of Type-1, Diabetes Mellitus, T1DM-induced cardiomyopathy.[220] It has been proposed that four potential mechanisms are responsible for this adverse effect due to FGF-21 deficiency.[3] First, FGF-21 deficiency results in an increased oxidative stress within cardiac. Second, increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-activated CD36 expression was seen, which led to increased plasma lipid uptake and accumulation into the cells. Third, decreased PGC1α protein expression was observed, which led to decreased FAO, thus promoting lipid uptake and accumulation in cardiomyocytes via the CD36 receptor on the cell membranes. Fourth, increased myocardial collagen accumulation was observed as shown by increased connective tissue growth factor. Another works also revealed that FGF-21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 upregulation in type 1 diabetic mice, which contributes to increased cardiac oxidative stress and remodeling, and accelerates the development and progression of DCM,[220] and the effects can be reversed by FGF-21 treatment.[219] Similar protection by FGF-21 was observed in mice with cardiac lipotoxicity induced by fatty acid.[219] Thus, FGF-21-induced cardioprotection in diabetic mice is mainly attributed to the prevention of lipotoxicity by FGF-21.[150] In addition, long-term treatment of FGF-21 prevented diabetic-induced cardiac dysfunction and fibrosis.[219]

Role of fibroblast growth factor-21 in cardiac hypertrophy and adverse cardiac remodeling

Hypertrophic remodeling characterized by enlarged cardiomyocytes is an adaptive response of the heart to certain stresses.[221] Moreover, it is also the leading cause of multiple cardiovascular problems including hypertension, myocardial ischemia, valvular disease, and cardiomyopathy.[222],[223],[224] Mature cardiomyocytes are considered to be terminally differentiated cells with no regenerative ability.[225],[226],[227]

Under stresses, cardiac hypertrophy is characterized by cardiomyocytes enlargement, rather than cells division,[228] and this phenomenon is accompanied by the increase of ECM and fibroblasts inside the heart.[229],[230] Recently, cardiac hypertrophy was reported to induce FGF-21 gene expression in the cardiomyocytes of mouse, and this was subjected to transcriptional regulation of the hepatic silent mating type information regulation 2 homolog 1/PPARα pathway.[146] Evidence fromin vivo studies demonstrate that continuous administration of isoproterenol via sc infusion for 7 days in FGF-21-KO mice-induced cardiomyopathy and led to myocardial infarction (MI), impaired cardiac metabolism, and loss of cardiac function in the rat heart.[146],[231] In turn, FGF-21-KO mice had greater heart weights and more severe cardiac dysfunction in response to isoproterenol infusion along with the induction of hypertrophic inflammatory markers.[146] However, administration of recombinant FGF-21 significantly prevented isoproterenol-induced cardiac hypertrophy damage in mice.[146] In a singlein vitro study, pretreatment with FGF-21 protects neonatal cardiomyocytes from phenylephrine-induced hypertrophy by promoting FAO gene expression, attenuating inflammation, and oxidative stress through the activation of Sirt1 and Erk1/2-CREB signaling pathways.[146] This study also demonstrated that the Sirt1-PPARα pathway plays an important role in the control of FGF-21 expression in the heart. Mechanistic studies also indicated that FGF-21 prevented cardiac hypertrophy by activating MAPK signaling via the activation of FGFR1c/β-klotho.[8],[146] In addition, FGF-21 prevented cardiac hypertrophy by promoting multiple antioxidant genes expressions (e.g., UCP2 and UCP3, also superoxide dismutase-2) and inhibiting the formation of reactive oxygen species in an autocrine manner.[232] Interestingly, in the other function, FGF-21 also reversed the adverse cardiac remodeling process, leading to improved left ventricular function in this chronic MI mice model.[144] In FGF-21-KO mice, it has been shown that FGF-21 attenuated cardiac hypertrophy by decreasing hypertrophic markers including atrial natriuretic factor and a skeletal actin[146] and by promoting proinflammatory pathways, oxidative stress, cardiac fibrosis, and impairing cardiac metabolism.[146],[232] Conversely, FGF-21 decreased the heart weight/body weight ratio and cardiomyocytes area and also improved cardiac function.[146],[232] Results confirmed that FGF-21 has a protective role against cardiac hypertrophy and remodeling.[3]

Role of fibroblast growth factor-21 in myocyte apoptosis and myocardial infarction

Myocardial ischemia, a disorder causing cardiomyocytes injury and MI and malfunction, activates adaptive responses enhancing myocardial tolerance to ischemia.[150] Liu et al. indicated that, in response to myocardial ischemia in the apoE−/−-, liver- and adipocytes-derived FGF-21 was upregulated and secreted into the circulation.[233] After interacting with FGFR1 in cardiomyocytes in the presence of β-klotho, FGF-21 activates its downstream kinases and proteins including PI3K, PKB/AKT, and Bcl2 antagonist of cell death (BAD), thereby reducing myocardial ischemia-induced apoptosis characterized by the reduction of caspase-3 activity.[234] However, the adaptive response was not found in FGF-21-deficient mice. Reversely, myocardial ischemic size was significantly smaller in FGF-21 transgenic mice than that in wild-type mice,[234] suggesting that upregulated endogenous FGF-21 derived from the liver and adipose tissue in response to myocardial injury-induced cardiac protection mediated by the activation of FGFR1/β-klotho-PI3K-Akt1-BAD signaling pathway.[150],[233] Although various growth factors and cytokines were upregulated during myocardial ischemia, the expression and secretion of cardiac FGF-21 had no alteration, implying that FGF-21 induces cardiac protection against myocardial ischemia in an endocrine rather than an autocrine manner.[233],[234] To date, a question of whether administration of exogenous FGF-21 can also induce cardiac protection during myocardial ischemia and if so whether the protection of exogenous FGF-21 against myocardial ischemia can be direct to the heart or cardiomyocytes appears. This question was answered by Patel et al.[147] They found that administration of exogenous FGF-21 induced significant cardioprotection and restored cardiac function following global ischemia in Langendorff-perfused rat hearts. Further study revealed that the inhibition of AKT, ERK1/2, and AMPK impaired FGF-21-induced antimyocardial ischemia effect in the hearts of obese Wistar rats, suggesting that the above kinases are involved in this cardioprotection of FGF-21.[147] Mechanistic studies also indicated that FGF-21-induced anti-apoptotic effectsin vitro andin vivo were mediated by ERK1/2-p38-MAPK-AMPK signaling pathway.[219] Moreover, FGF-21 prevented oxidative stress[232],[235] and also increased the energy supply for cardiomyocytes under ischemia-reperfusion (I/R) injury conditions.[235] In FGF-21-KO mice, FGF-21 given intravenously at 50 ng/g per day for 3 days with the first dose being given immediately after I/R injury (IZ – 30 min, RZ1 – 30 days) had been shown to protect the heart from apoptosis and MI and also increase cardiac function.[234]

In the acute MI, an intravenous injection of recombinant mouse FGF-21 10 ng/g in a single dose immediately post-MI decreased the infarction area.[233] Moreover, in chronic MI (2 weeks) and adiponectin-KO mice models, it was demonstrated that FGF-21 protein derived from the skeletal muscles protected the heart from apoptosis through adiponectin signaling.[144] The mechanistic study revealed that FGF-21-induced protection against I/R injury in cardiac cells mainly depended on the activation of AKT-GSK-3β-caspase-3 signaling pathway by promoting the energy supply and reducing inflammation.[235] It was proposed that the activation of these pathways would lead to a decrease in the myocardial infarct area and increase cardiac function.[147],[234] In an ex vivo model of global cardiac ischemia, it has been shown that recombinant rat FGF-21 infusion 10 min before ischemia can protect the heart from I/R injury by decreasing MI and increasing the cardiac function through activation of the MAPK-PI3K-AKT signaling pathway.[147] All of these findings indicate that exogenous and endogenous FGF-21 play an important role in protecting the heart from apoptosis via several pathways, including PI3K-AKT1-BAD and AKT-GSK3 β-caspase 3-dependent mechanisms, leading to decreased infarction and increased left ventricular function under I/R injury, lipotoxic, and MI conditions.


  The Role of Serum Fibroblast Growth Factor-21 Level as Biologic Markers of Cardiovascular Diseases Top


Serum FGF-21 levels are increased in chronic kidney disease and acute kidney dysfunction, suggesting that renal excretion is a major route for the elimination of FGF-21.[236] Serum FGF-21 levels are also significantly increased in CHD. Serum FGF-21 levels in CHD patients with diabetes, hypertension, or both are higher than those in patients without these comorbidities. High serum FGF-21 levels are associated with adverse lipid profiles in CHD patients, indicating that the paradoxical increase in the serum FGF-21 levels in CHD patients is a compensatory response or resistance to FGF-21.[185] Serum FGF-21 levels are positively correlated with carotid intima-media thickness (IMT) in women, but not in men, indicating that elevated serum FGF-21 levels in women are an independent risk factor for increased carotid IMT.[186] Preeclampsia, a serious cardiovascular complication in pregnancy, is associated with an increased future metabolic and cardiovascular risk. Serum FGF-21 levels are significantly increased in patients with preeclampsia during pregnancy.[237]

Furthermore, serum FGF-21 levels are significantly increased in human mitochondrial disease and the best predictor of mitochondrial disease among classical indicators, including creatine kinase, lactate, and pyruvate.[238],[239] Mitochondrial disease caused by dysfunctional mitochondria is a group of disorders with highly variable phenotypes, including mitochondrial myopathy, diabetes mellitus, deafness, optic neuropathy, and multiple sclerosis-type disease. Serum FGF-21 levels are also significantly increased in patients with obese and type 2 diabetes, suggesting the direct positive metabolic effects of FGF-21.[240],[241],[242],[243],[244] Anorexia nervosa (AN) is an eating disorder that is characterized by a low weight and food restriction. Serum FGF-21 levels are significantly decreased in AN, suggesting that FGF-21 is involved in the pathophysiology of or a complex adaptive response to AN.[245] Cushing's syndrome is caused by prolonged exposure to inappropriately high levels of glucocorticoids. Serum FGF-21 levels are increased in patients with Cushing's syndrome. Increased serum FGF-21 levels are attributed to their excessive fat accumulation and related metabolic abnormalities, but not to the direct effects of cortisol on the production of FGF-21.[246] BAT, which contains a markedly higher number of mitochondria, generates body heat in animals without shivering. Since BAT is expected to markedly contribute to energy homeostasis in humans, it may represent a therapeutic target of obesity. Serum FGF-21 levels are associated with BAT activity, indicating a novel mechanism by which BAT activity may be enhanced.[247] Serum FGF-21 levels are also increased in patients with nonalcoholic fatty liver disease (NAFLD), which supports the role of FGF-21 as a key regulator of hepatic lipid metabolism.[248] In contrast to adults with NAFLD, serum FGF-19 and FGF-21 levels are inversely associated with hepatic damage in children with NAFLD, providing insights for a better understanding of the progression of NAFLD.[249] Serum FGF-21 levels are also increased in chronic hepatitis C (CHC) patients with steatosis and are associated with the steatosis grade, which may be a useful diagnostic marker for determining hepatic steatosis in CHC.[250] Hepatitis C (HC) is an infectious disease that is caused by the HC virus. Serum FGF-21 levels are significantly increased in patients with sepsis and systemic inflammatory response syndrome (SIRS), suggesting a role for FGF-21 in inflammation.[251] Sepsis is an illness in which the body has a severe response to infection. SIRS is an inflammatory state in the whole body due to the response of the immune system to infection. SIRS is also closely related to sepsis.

Furthermore, serum FGF-21 levels are significantly increased in patients with rheumatoid arthritis (RA), indicating the compensatory response of FGF-21 to inflammation and immune response.[252] RA is a chronic inflammatory disease in small hand and foot joints.


  Conclusion Top


FGF family members have a potent intracellular, paracrine, and endocrine activity with multiple pleiotropic activities. FGF-21 is a member of FGF family that is produced predominantly in the liver and is also produced and secreted by cardiac cells. It acts in an FGFR-dependent manner with β-Klotho as a cofactor. Multiple beneficial metabolic effects of FGF-21 have been previously demonstrated in experimental and animal models, suggesting that FGF-21 is not a simple marker of cardiovascular risk but may have a protective effect on the cardiovascular system, contributing to a reduction in risk. Evidence has shown that FGF-21 is crucial for cardioprotection in myocardial hypertrophy, ischemia, DCM, and I/R injury. Evidence reported so far suggests that FGF-21 possesses favorable metabolic effects not only on carbohydrate but also on lipid metabolism, showing antihyperglycemic and antihyperlipidemic properties promoting insulin sensitivity and thermogenesis. In humans, high FGF-21 levels have been invariably linked to insulin-resistant states, such as glucose intolerance, Diabetes Mellitus Metabolic Syndrome (MetS), and obesity, as well as some of their complications, such as CHD, indicating a possible compensatory elevation of FGF-21 to overcome insulin resistance. Based on the previous studies, as it has been suggested by some authors, FGF-21 represents a novel and attractive therapeutic agent. In this regard, the pharmacological use of recombinant human FGF-21, FGF-21 analogs or agonists, and drugs that increase circulation levels of endogenous FGF-21 might be of interest in the therapeutic armamentarium against disease states associated with insulin resistance, mainly DM2, obesity, polycystic ovary syndrome, and hepatic steatosis. Further investigations in patients with the above-mentioned states and other metabolic disorders associated with insulin resistance are, therefore, required to clarify the true role of the potential therapeutic applications of this new metabolic hormone.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Itoh N, Ohta H, Konishi M. Endocrine FGFs: Evolution, physiology, pathophysiology, and pharmacotherapy. Front Endocrinol (Lausanne) 2015;6:154.  Back to cited text no. 1
    
2.
Di Lisa F, Itoh N. Cardiac Fgf21 synthesis and release: An autocrine loop for boosting up antioxidant defenses in failing hearts. Cardiovasc Res 2015;106:1-3.  Back to cited text no. 2
    
3.
Tanajak P, Chattipakorn SC, Chattipakorn N. Effects of fibroblast growth factor 21 on the heart. J Endocrinol 2015;227:R13-30.  Back to cited text no. 3
    
4.
McKeehan WL, Wang F, Kan M. The heparan sulfate-fibroblast growth factor family: Diversity of structure and function. Prog Nucleic Acid Res Mol Biol 1998;59:135-76.  Back to cited text no. 4
    
5.
Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004;20:563-9.  Back to cited text no. 5
    
6.
Bae KH, Kim JG, Park KG. Transcriptional regulation of fibroblast growth factor 21 expression. Endocrinol Metab (Seoul) 2014;29:105-11.  Back to cited text no. 6
    
7.
Itoh N, Ornitz DM. Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease. J Biochem 2011;149:121-30.  Back to cited text no. 7
    
8.
Itoh N, Ohta H. Pathophysiological roles of FGF signaling in the heart. Front Physiol 2013;4:247.  Back to cited text no. 8
    
9.
Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627-35.  Back to cited text no. 9
    
10.
Dale JK, Malapert P, Chal J, Vilhais-Neto G, Maroto M, Johnson T, et al. Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev Cell 2006;10:355-66.  Back to cited text no. 10
    
11.
Itoh N. The Fgf families in humans, mice, and zebrafish: Their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull 2007;30:1819-25.  Back to cited text no. 11
    
12.
O'Leary DD, Chou SJ, Sahara S. Area patterning of the mammalian cortex. Neuron 2007;56:252-69.  Back to cited text no. 12
    
13.
Lu SY, Sheikh F, Sheppard PC, Fresnoza A, Duckworth ML, Detillieux KA, et al. FGF-16 is required for embryonic heart development. Biochem Biophys Res Commun 2008;373:270-4.  Back to cited text no. 13
    
14.
Goetz R, Dover K, Laezza F, Shtraizent N, Huang X, Tchetchik D, et al. Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. J Biol Chem 2009;284:17883-96.  Back to cited text no. 14
    
15.
Goriely A, Hansen RM, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009;41:1247-52.  Back to cited text no. 15
    
16.
Eriksson AE, Cousens LS, Weaver LH, Matthews BW. Three-dimensional structure of human basic fibroblast growth factor. Proc Natl Acad Sci U S A 1991;88:3441-5.  Back to cited text no. 16
    
17.
Zhang JD, Cousens LS, Barr PJ, Sprang SR. Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta. Proc Natl Acad Sci U S A 1991;88:3446-50.  Back to cited text no. 17
    
18.
Zhu X, Komiya H, Chirino A, Faham S, Fox GM, Arakawa T, et al. Three-dimensional structures of acidic and basic fibroblast growth factors. Science 1991;251:90-3.  Back to cited text no. 18
    
19.
Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 2005;16:107-37.  Back to cited text no. 19
    
20.
Plotnikov AN, Hubbard SR, Schlessinger J, Mohammadi M. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 2000;101:413-24.  Back to cited text no. 20
    
21.
Yeh BK, Igarashi M, Eliseenkova AV, Plotnikov AN, Sher I, Ron D, et al. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc Natl Acad Sci U S A 2003;100:2266-71.  Back to cited text no. 21
    
22.
Olsen SK, Li JY, Bromleigh C, Eliseenkova AV, Ibrahimi OA, Lao Z, et al. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev 2006;20:185-98.  Back to cited text no. 22
    
23.
Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem 1996;271:15292-7.  Back to cited text no. 23
    
24.
Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006;281:15694-700.  Back to cited text no. 24
    
25.
Beenken A, Mohammadi M. The FGF family: Biology, pathophysiology and therapy. Nat Rev Drug Discov 2009;8:235-53.  Back to cited text no. 25
    
26.
Krejci P, Prochazkova J, Bryja V, Kozubik A, Wilcox WR. Molecular pathology of the fibroblast growth factor family. Hum Mutat 2009;30:1245-55.  Back to cited text no. 26
    
27.
Goetz R, Mohammadi M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 2013;14:166-80.  Back to cited text no. 27
    
28.
Ornitz D, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2005;4:215-66.  Back to cited text no. 28
    
29.
Jaye M, Schlessinger J, Dionne CA. Fibroblast growth factor receptor tyrosine kinases: Molecular analysis and signal transduction. Biochim Biophys Acta 1992;1135:185-99.  Back to cited text no. 29
    
30.
Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993;60:1-41.  Back to cited text no. 30
    
31.
Oulion S, Bertrand S, Escriva H. Evolution of the FGF Gene Family. Int J Evol Biol 2012;2012:298147.  Back to cited text no. 31
    
32.
Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci 2011;68:951-64.  Back to cited text no. 32
    
33.
Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M. Structural basis for FGF receptor dimerization and activation. Cell 1999;98:641-50.  Back to cited text no. 33
    
34.
Stauber DJ, DiGabriele AD, Hendrickson WA. Structural interactions of fibroblast growth factor receptor with its ligands. Proc Natl Acad Sci U S A 2000;97:49-54.  Back to cited text no. 34
    
35.
Wang F, Kan M, Yan G, Xu J, McKeehan WL. Alternately spliced NH2-terminal immunoglobulin-like Loop I in the ectodomain of the fibroblast growth factor (FGF) receptor 1 lowers affinity for both heparin and FGF-1. J Biol Chem 1995;270:10231-5.  Back to cited text no. 35
    
36.
Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, et al. Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc Natl Acad Sci U S A 2004;101:935-40.  Back to cited text no. 36
    
37.
Johnson D, Lu J, Chen H, Werner S, Williams L. The human fibroblast growth factor receptor genes: A common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol 1991;11:4627-34.  Back to cited text no. 37
    
38.
Miki T, Bottaro D, Fleming T, Smith C, Burgess W, Chan A, et al. Determination of ligand-binding specificity by alternative splicing: Two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 1992;89:246-50.  Back to cited text no. 38
    
39.
Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol 1993;158:475-86.  Back to cited text no. 39
    
40.
Kharitonenkov A. FGF-21/FGF-21 receptor interaction and activation is determined by beta Klotho. J Cell Physiol 2008;215:1-7.  Back to cited text no. 40
    
41.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF-23. Nature 2006;444:770-4.  Back to cited text no. 41
    
42.
Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M, et al. Beta Klotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol 2008;22:1006-14.  Back to cited text no. 42
    
43.
Rapraeger A, Krufka A, Olwin B. Requirement of heparan sulfate for beta FGF-mediated fibroblast growth and myoblast differentiation. Science 1991;252:1705-8.  Back to cited text no. 43
    
44.
Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991;64:841-8.  Back to cited text no. 44
    
45.
Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P. Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol 1992;12:240-7.  Back to cited text no. 45
    
46.
Whitelock JM, Iozzo RV. Heparan sulfate: A complex polymer charged with biological activity. Chem Rev 2005;105:2745-64.  Back to cited text no. 46
    
47.
Mohammadi M, Olsen SK, Goetz R. A protein canyon in the FGF-FGF receptor dimer selects from an à la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 2005;15:506-16.  Back to cited text no. 47
    
48.
Makarenkova HP, Hoffman MP, Beenken A, Eliseenkova AV, Meech R, Tsau C, et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci Signal 2009;2:ra55.  Back to cited text no. 48
    
49.
Saksela O, Moscatelli D, Sommer A, Rifkin DB. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol 1988;107:743-51.  Back to cited text no. 49
    
50.
Häcker U, Nybakken K, Perrimon N. Heparan sulphate proteoglycans: The sweet side of development. Nat Rev Mol Cell Biol 2005;6:530-41.  Back to cited text no. 50
    
51.
Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH, Kimata K. Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 2004;279:12346-54.  Back to cited text no. 51
    
52.
Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 2000;6:743-50.  Back to cited text no. 52
    
53.
Lin X, Buff EM, Perrimon N, Michelson AM. Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Development 1999;126:3715-23.  Back to cited text no. 53
    
54.
Forsberg E, Kjellén L. Heparan sulfate: Lessons from knockout mice. J Clin Invest 2001;108:175-80.  Back to cited text no. 54
    
55.
Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007;27:3417-28.  Back to cited text no. 55
    
56.
Chen H, Ma J, Li W, Eliseenkova AV, Xu C, Neubert TA, et al. A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol Cell 2007;27:717-30.  Back to cited text no. 56
    
57.
Mohammadi M, Dikic I, Sorokin A, Burgess WH, Jaye M, Schlessinger J. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol 1996;16:977-89.  Back to cited text no. 57
    
58.
Furdui CM, Lew ED, Schlessinger J, Anderson KS. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell 2006;21:711-7.  Back to cited text no. 58
    
59.
Chen H, Xu CF, Ma J, Eliseenkova AV, Li W, Pollock PM, et al. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc Natl Acad Sci U S A 2008;105:19660-5.  Back to cited text no. 59
    
60.
Mohammadi M, Dionne CA, Li W, Li N, Spivak T, Honegger AM, et al. Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature 1992;358:681-4.  Back to cited text no. 60
    
61.
Peters K, Marie J, Wilson E, Ives H, Escobedo J, Del Rosario M, et al. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+flux but not mitogenesis. Nature 1992;358:678-81.  Back to cited text no. 61
    
62.
Seo JH, Suenaga A, Hatakeyama M, Taiji M, Imamoto A. Structural and functional basis of a role for CRKL in a fibroblast growth factor 8-induced feed-forward loop. Mol Cell Biol 2009;29:3076-87.  Back to cited text no. 62
    
63.
Divecha N, Irvine RF. Phospholipid signaling. Cell 1995;80:269-78.  Back to cited text no. 63
    
64.
Huang J, Mohammadi M, Rodrigues GA, Schlessinger J. Reduced activation of RAF-1 and MAP kinase by a fibroblast growth factor receptor mutant deficient in stimulation of phosphatidylinositol hydrolysis. J Biol Chem 1995;270:5065-72.  Back to cited text no. 64
    
65.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211-25.  Back to cited text no. 65
    
66.
Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997;89:693-702.  Back to cited text no. 66
    
67.
Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, et al. Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Mol Cell 2000;6:921-9.  Back to cited text no. 67
    
68.
Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, et al. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol Cell Biol 2000;20:979-89.  Back to cited text no. 68
    
69.
Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci U S A 2001;98:6074-9.  Back to cited text no. 69
    
70.
Hadari YR, Kouhara H, Lax I, Schlessinger J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol 1998;18:3966-73.  Back to cited text no. 70
    
71.
Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 2005;16:233-47.  Back to cited text no. 71
    
72.
Kuro-o M. Klotho and β-Klotho. Adv Exp Med Biol 2012;728:25-40.  Back to cited text no. 72
    
73.
Beenken A, Mohammadi M. The structural biology of the FGF19 subfamily. Adv Exp Med Biol 2012;728:1-24.  Back to cited text no. 73
    
74.
Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem 2010;285:5165-70.  Back to cited text no. 74
    
75.
Itoh N. Fibroblast growth factors 21 as a hepatokine, adipokine, and myokine in metabolism and diseases. Frontiers Endocrinol Diabetes 2014;5:1-4.  Back to cited text no. 75
    
76.
Lew ED, Furdui CM, Anderson KS, Schlessinger J. The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci Signal 2009;2:ra6.  Back to cited text no. 76
    
77.
Dudka AA, Sweet SM, Heath JK. Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification. Cancer Res 2010;70:3391-401.  Back to cited text no. 77
    
78.
Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, et al. A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol Cell Biol 1991;11:5068-78.  Back to cited text no. 78
    
79.
Xu H, Lee KW, Goldfarb M. Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins. J Biol Chem 1998;273:17987-90.  Back to cited text no. 79
    
80.
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 2005;16:139-49.  Back to cited text no. 80
    
81.
Turner N, Grose R. Fibroblast growth factor signalling: From development to cancer. Nat Rev Cancer 2010;10:116-29.  Back to cited text no. 81
    
82.
Silva PN, Altamentova SM, Kilkenny DM, Rocheleau JV. Fibroblast growth factor receptor like-1 (FGFRL1) interacts with SHP-1 phosphatase at insulin secretory granules and induces beta-cell ERK1/2 protein activation. J Biol Chem 2013;288:17859-70.  Back to cited text no. 82
    
83.
Amann R, Wyder S, Slavotinek AM, Trueb B. The FgfrL1 receptor is required for development of slow muscle fibers. Dev Biol 2014;394:228-41.  Back to cited text no. 83
    
84.
Moon AM, Guris DL, Seo JH, Li L, Hammond J, Talbot A, et al. Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell 2006;10:71-80.  Back to cited text no. 84
    
85.
Larsson H, Klint P, Landgren E, Claesson-Welsh L. Fibroblast Growth Factor receptor-1-mediated endothelial cell proliferation is dependent on the Src homology (SH) 2/SH3 domain-containing adaptor protein Crk. J Biol Chem 1999;274:25726-34.  Back to cited text no. 85
    
86.
House SL, Branch K, Newman G, Doetschman T, Schultz Jel J. Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. Am J Physiol Heart Circ Physiol 2005;289:H2167-75.  Back to cited text no. 86
    
87.
Liao S, Porter D, Scott A, Newman G, Doetschman T, Schultz Jel J. The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: The role of JNK signaling. J Mol Cell Cardiol 2007;42:106-20.  Back to cited text no. 87
    
88.
Kanazawa S, Fujiwara T, Matsuzaki S, Shingaki K, Taniguchi M, Miyata S, et al. Beta-FGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One 2010;5:e12228.  Back to cited text no. 88
    
89.
Tsang M, Dawid I. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci STKE 2004;2004:pe17.  Back to cited text no. 89
    
90.
Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb M. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 1996;15:4629-42.  Back to cited text no. 90
    
91.
Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J. The docking protein Gab1 is an essential component of an indirect mechanism for Fibroblast Growth Factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol Cell Biol 2004;24:5657-66.  Back to cited text no. 91
    
92.
Firnberg N, Neubuser A. FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. Dev Biol 2002;247:237-50.  Back to cited text no. 92
    
93.
Raible F, Brand M. Tight transcriptional control of the ETS domain factors Erm and Pea3 by Fgf signaling during early zebrafish development. Mech Dev 2001;107:105-17.  Back to cited text no. 93
    
94.
Roehl H, Nüsslein-Volhard C. Zebrafish pea3 and erm are general targets of FGF8 signaling. Curr Biol 2001;11:503-7.  Back to cited text no. 94
    
95.
Brent A, Tabin C. FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression. Development 2004;131:3885-96.  Back to cited text no. 95
    
96.
Manning BD, Cantley LC. AKT/PKB signaling: Navigating downstream. Cell 2007;129:1261-74.  Back to cited text no. 96
    
97.
Reilly JF, Mickey G, Maher PA. Association of fibroblast growth factor receptor 1 with the adaptor protein Grb14. Characterization of a new receptor binding partner. J Biol Chem 2000;275:7771-8.  Back to cited text no. 97
    
98.
Browaeys-Poly E, Blanquart C, Perdereau D, Antoine AF, Goenaga D, Luzy JP, et al. Grb14 inhibits FGF receptor signaling through the regulation of PLCγ recruitment and activation. FEBS Lett 2010;584:4383-8.  Back to cited text no. 98
    
99.
Cross MJ, Lu L, Magnusson P, Nyqvist D, Holmqvist K, Welsh M, et al. The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells. Mol Biol Cell 2002;13:2881-93.  Back to cited text no. 99
    
100.
Su W, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, et al. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 1997;386:288-92.  Back to cited text no. 100
    
101.
Yang X, Qiao D, Meyer K, Pier T, Keles S, Friedl A. Angiogenesis induced by signal transducer and activator of transcription 5A (STAT5A) is dependent on autocrine activity of proliferin. J Biol Chem 2012;287:6490-502.  Back to cited text no. 101
    
102.
Hart KC, Robertson SC, Kanemitsu MY, Meyer AN, Tynan JA, Donoghue DJ. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 2000;19:3309-20.  Back to cited text no. 102
    
103.
Heath C, Cross NC. Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. J Biol Chem 2004;279:6666-73.  Back to cited text no. 103
    
104.
Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy D, Basilico C. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999;13:1361-6.  Back to cited text no. 104
    
105.
Leaman DW, Pisharody S, Flickinger TW, Commane MA, Schlessinger J, Kerr IM, et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol 1996;16:369-75.  Back to cited text no. 105
    
106.
Yang X, Qiao D, Meyer K, Friedl A. Signal transducers and activators of transcription mediate fibroblast growth factor-induced vascular endothelial morphogenesis. Cancer Res 2009;69:1668-77.  Back to cited text no. 106
    
107.
Wu DQ, Kan MK, Sato GH, Okamoto T, Sato JD. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. J Biol Chem 1991;266:16778-85.  Back to cited text no. 107
    
108.
Haugsten EM, Zakrzewska M, Brech A, Pust S, Olsnes S, Sandvig K, et al. Clathrin- and dynamin-independent endocytosis of FGFR3--implications for signalling. PLoS One 2011;6:e21708.  Back to cited text no. 108
    
109.
Auciello G, Cunningham DL, Tatar T, Heath JK, Rappoport JZ. Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8. J Cell Sci 2013;126:613-24.  Back to cited text no. 109
    
110.
Francavilla C, Rigbolt KT, Emdal KB, Carraro G, Vernet E, Bekker-Jensen DB, et al. Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs. Mol Cell 2013;51:707-22.  Back to cited text no. 110
    
111.
Dikic I, Giordano S. Negative receptor signalling. Curr Opin Cell Biol 2003;15:128-35.  Back to cited text no. 111
    
112.
Guy GR, Jackson RA, Yusoff P, Chow SY. Sprouty proteins: Modified modulators, matchmakers or missing links? J Endocrinol 2009;203:191-202.  Back to cited text no. 112
    
113.
Yu T, Yaguchi Y, Echevarria D, Martinez S, Basson MA. Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum. Development 2011;138:2957-68.  Back to cited text no. 113
    
114.
Thisse B, Thisse C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 2005;287:390-402.  Back to cited text no. 114
    
115.
Fürthauer M, Lin W, Ang SL, Thisse B, Thisse C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nat Cell Biol 2002;4:170-4.  Back to cited text no. 115
    
116.
Tsang M, Friesel R, Kudoh T, Dawid IB. Identification of Sef, a novel modulator of FGF signalling. Nat Cell Biol 2002;4:165-9.  Back to cited text no. 116
    
117.
Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell 2004;7:33-44.  Back to cited text no. 117
    
118.
Kovalenko D, Yang X, Chen PY, Nadeau RJ, Zubanova O, Pigeon K, et al. A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling. Cell Signal 2006;18:1958-66.  Back to cited text no. 118
    
119.
Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, et al. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science 1998;280:1262-5.  Back to cited text no. 119
    
120.
Li C, Scott DA, Hatch E, Tian X, Mansour SL. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 2007;134:167-76.  Back to cited text no. 120
    
121.
Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, et al. Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J 2008;412:287-98.  Back to cited text no. 121
    
122.
Dickinson RJ, Eblaghie MC, Keyse SM, Morriss-Kay GM. Expression of the ERK-specific MAP kinase phosphatase PYST1/MKP3 in mouse embryos during morphogenesis and early organogenesis. Mech Dev 2002;113:193-6.  Back to cited text no. 122
    
123.
Eblaghie MC, Lunn JS, Dickinson RJ, Münsterberg AE, Sanz-Ezquerro JJ, Farrell ER, et al. Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos. Curr Biol 2003;13:1009-18.  Back to cited text no. 123
    
124.
Wong A, Lamothe B, Lee A, Schlessinger J, Lax I. FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proc Natl Acad Sci U S A 2002;99:6684-9.  Back to cited text no. 124
    
125.
Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ. FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone 2008;42:1032-9.  Back to cited text no. 125
    
126.
Ahmed Z, George R, Lin CC, Suen KM, Levitt JA, Suhling K, et al. Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function. Cell Signal 2010;22:23-33.  Back to cited text no. 126
    
127.
Ahmed Z, Lin CC, Suen KM, Melo FA, Levitt JA, Suhling K, et al. Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. J Cell Biol 2013;200:493-504.  Back to cited text no. 127
    
128.
Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203-6.  Back to cited text no. 128
    
129.
Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, et al. Structures of β-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling. Nature 2018;553:501-5.  Back to cited text no. 129
    
130.
Potthoff M, Inagaki T, Satapati S, Ding X, He T, Goetz R, et al. FGF-21 induces PGC-1 alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 2009;106:10853-8.  Back to cited text no. 130
    
131.
Adams AC, Kharitonenkov A. FGF21: The center of a transcriptional nexus in metabolic regulation. Curr Diabetes Rev 2012;8:285-93.  Back to cited text no. 131
    
132.
Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426-37.  Back to cited text no. 132
    
133.
Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPAR alpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5:415-25.  Back to cited text no. 133
    
134.
Hondares E, Rosell M, Gonzalez F, Giralt M, Iglesias R, Villarroya F. Hepatic FGF 21 expression is induced at birth via PPAR α in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010;11:206-12.  Back to cited text no. 134
    
135.
Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol 2008;74:403-12.  Back to cited text no. 135
    
136.
Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 2008;28:188-200.  Back to cited text no. 136
    
137.
Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010;24:2050-64.  Back to cited text no. 137
    
138.
Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, et al. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 2011;286:34559-66.  Back to cited text no. 138
    
139.
Ding X, Boney-Montoya J, Owen B, Bookout A, Coate K, Mangelsdorf D, et al. Beta Klotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012;16:387-93.  Back to cited text no. 139
    
140.
Véniant MM, Hale C, Helmering J, Chen MM, Stanislaus S, Busby J, et al. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLoS One 2012;7:e40164.  Back to cited text no. 140
    
141.
Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): Results from two phase 3 randomised trials. Lancet 2015;386:541-51.  Back to cited text no. 141
    
142.
Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983-90.  Back to cited text no. 142
    
143.
Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013;19:83-92.  Back to cited text no. 143
    
144.
Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K, et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem Biophys Res Commun 2015;459:124-30.  Back to cited text no. 144
    
145.
Kharitonenkov A. FGFs and metabolism. Curr Opin Pharmacol 2009;9:805-10.  Back to cited text no. 145
    
146.
Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013;4:2019.  Back to cited text no. 146
    
147.
Patel V, Adya R, Chen J, Ramanjaneya M, Bari M, Bhudia S, et al. Novel insights into the cardio-protective effects of FGF-21 in lean and obese rat hearts. PLoS One 2014;9:e87102.  Back to cited text no. 147
    
148.
Ito S, Kinoshita S, Shiraishi N, Nakagawa S, Sekine S, Fujimori T, et al. Molecular cloning and expression analyses of mouse β klotho, which encodes a novel klotho family protein. Mech Dev 2000;98:115-9.  Back to cited text no. 148
    
149.
Iglesias P, Selgas R, Romero S, Díez JJ. Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21. Eur J Endocrinol 2012;167:301-9.  Back to cited text no. 149
    
150.
Peng C, Fangfang Z, Lechu Y, Xiufei L, Luqing H, Xiaokun L, et al. Physiological and pharmacological roles of FGF-21 in cardiovascular diseases. J Diabetes Res 2016;2016:1-8.  Back to cited text no. 150
    
151.
Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt K, Goetz R, et al. Beta klotho is required for metabolic activity of fibroblast growth factor 21. PNAS 2007;104:7432-7.  Back to cited text no. 151
    
152.
Yie J, Hecht R, Patel J, Stevens J, Wang W, Hawkins N, et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett 2009;583:19-24.  Back to cited text no. 152
    
153.
Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T, Wang M, et al. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 2012;153:69-80.  Back to cited text no. 153
    
154.
Li H, Zhang J, Jia W. Fibroblast growth factor 21: A novel metabolic regulator from pharmacology to physiology. Front Med 2013;7:25-30.  Back to cited text no. 154
    
155.
Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: From pharmacology to physiology. Am J Clin Nutr 2010;91:254S-257S.  Back to cited text no. 155
    
156.
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1-22.  Back to cited text no. 156
    
157.
Sakakibara I, Fujino T, Ishii M, Tanaka T, Shimosawa T, Miura S, et al. Fasting induced hypothermia and reduced energy production in mice lacking acetylCoA synthetase 2. Cell Metab 2009;9:191-202.  Back to cited text no. 157
    
158.
Inagaki T. Research perspectives on the regulation and physiological functions of FGF21 and its association with NAFLD. Front Endocrinol (Lausanne) 2015;6:147.  Back to cited text no. 158
    
159.
Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, et al. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006;55:2470-8.  Back to cited text no. 159
    
160.
Fisher F, Kleiner S, Douris N, Fox E, Mepani R, Verdeguer F, et al. FGF 21 regulates PGC-1 alpha and browning of white adipose tissues in adaptive thermogenesis. Gene Dev 2012;26:271-81.  Back to cited text no. 160
    
161.
Berglund ED, Li CY, Bina HA, Lynes SE, Michael MD, Shanafelt AB, et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 2009;150:4084-93.  Back to cited text no. 161
    
162.
Berglund ED, Kang L, Lee-Young RS, Hasenour CM, Lustig DG, Lynes SE, et al. Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo. Am J Physiol Endocrinol Metab 2010;299:E607-14.  Back to cited text no. 162
    
163.
Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774-81.  Back to cited text no. 163
    
164.
Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009;58:250-9.  Back to cited text no. 164
    
165.
Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008;149:6018-27.  Back to cited text no. 165
    
166.
Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010;59:2781-9.  Back to cited text no. 166
    
167.
Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL, Rahmouni K, et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014;20:670-7.  Back to cited text no. 167
    
168.
Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 2008;8:77-83.  Back to cited text no. 168
    
169.
Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 2013;19:1153-6.  Back to cited text no. 169
    
170.
Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc Natl Acad Sci U S A 2012;109:3143-8.  Back to cited text no. 170
    
171.
Bornstein S, Brown SA, Le PT, Wang X, DeMambro V, Horowitz MC, et al. FGF-21 and skeletal remodeling during and after lactation in C57BL/6J mice. Endocrinology 2014;155:3516-26.  Back to cited text no. 171
    
172.
Zhang J, Kaasik K, Blackburn MR, Lee CC. Constant darkness is a circadian metabolic signal in mammals. Nature 2006;439:340-3.  Back to cited text no. 172
    
173.
Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 2012;1:e00065.  Back to cited text no. 173
    
174.
Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013;19:1147-52.  Back to cited text no. 174
    
175.
Nelson B, Ding X, Boney-Montoya J, Gerard R, Kliewer S, Andrews M. Metabolic hormone FGF-21 is induced in ground squirrels during hibernation but its overexpression is not sufficient to cause torpor. PLoS One 2013;8:e53574.  Back to cited text no. 175
    
176.
Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012;7:e49452.  Back to cited text no. 176
    
177.
Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302-9.  Back to cited text no. 177
    
178.
Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011;17:736-40.  Back to cited text no. 178
    
179.
Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI, Arumugam M, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 2014;124:515-27.  Back to cited text no. 179
    
180.
Lee P, Werner CD, Kebebew E, Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes (Lond) 2014;38:170-6.  Back to cited text no. 180
    
181.
Véniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 2015;21:731-8.  Back to cited text no. 181
    
182.
Samms R, Smith D, Cheng C, Antonellis P, Perfield J, Kharitonenkov A. Discrete aspects of FGF-21 in vivo pharmacology do not require UCP1. Cell Rep 2015;11:991-9.  Back to cited text no. 182
    
183.
Lusis AJ. Atherosclerosis. Nature 2000;407:233-41.  Back to cited text no. 183
    
184.
Davignon J. Advances in lipid-lowering therapy in atherosclerosis. Adv Exp Med Biol 2001;498:49-58.  Back to cited text no. 184
    
185.
Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One 2010;5:e15534.  Back to cited text no. 185
    
186.
Chow WS, Xu A, Woo YC, Tso AW, Cheung SC, Fong CH, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013;33:2454-9.  Back to cited text no. 186
    
187.
Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 2015;131:1861-71.  Back to cited text no. 187
    
188.
Wu X, Lü Y, Fu K, Wang S, Zhao D, Peng H, et al. Impact of exogenous fibroblast growth factor 21 on atherosclerosis in apolipoprotein E deficient mice. Zhonghua Xin Xue Guan Bing Za Zhi 2014;42:126-31.  Back to cited text no. 188
    
189.
Wu X, Qi Y, Chang J, Lu W, Zhang J, Wang S, et al. Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice. Heart Vessels 2015;30:657-68.  Back to cited text no. 189
    
190.
Jin L, Lin Z, Xu A. Fibroblast growth factor 21 protects against atherosclerosis via fine-tuning the multiorgan crosstalk. Diabetes Metab J 2016;40:22-31.  Back to cited text no. 190
    
191.
Kobashigawa Y, Amano S, Yoza K, Himeno R, Amemiya S, Morioka H, et al. Nuclear magnetic resonance analysis of the conformational state of cancer mutant of fibroblast growth factor receptor 1 tyrosine kinase domain. Genes Cells 2016;21:350-7.  Back to cited text no. 191
    
192.
Zhu W, Wang C, Liu L, Li Y, Li X, Cai J, et al. Effects of fibroblast growth factor 21 on cell damagein vitro and atherosclerosis in vivo. Can J Physiol Pharmacol 2014;92:927-35.  Back to cited text no. 192
    
193.
Bhatia SK. Tissue engineering for clinical applications. Biotechnol J 2010;5:1309-23.  Back to cited text no. 193
    
194.
Faxon DP, Creager MA, Smith SC Jr., Pasternak RC, Olin JW, Bettmann MA, et al. Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic Vascular Disease Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2004;109:2595-604.  Back to cited text no. 194
    
195.
Akadam-Teker B, Kurnaz O, Coskunpinar E, Daglar-Aday A, Kucukhuseyin O, Cakmak HA, et al. The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease. Gene 2013;528:93-8.  Back to cited text no. 195
    
196.
Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, et al. The vascular endothelium and human diseases. Int J Biol Sci 2013;9:1057-69.  Back to cited text no. 196
    
197.
Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine: A chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A 1988;85:2805-9.  Back to cited text no. 197
    
198.
Frostegård J, Haegerstrand A, Gidlund M, Nilsson J. Biologically modified LDL increases the adhesive properties of endothelial cells. Atherosclerosis 1991;90:119-26.  Back to cited text no. 198
    
199.
Lindner V, Lappi DA, Baird A, Majack RA, Reidy MA. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res 1991;68:106-13.  Back to cited text no. 199
    
200.
Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Nerem RM. The pathogenesis of atherosclerosis: An overview. Clin Cardiol 1991;14:I1-16.  Back to cited text no. 200
    
201.
Yui S, Sasaki T, Miyazaki A, Horiuchi S, Yamazaki M. Induction of murine macrophage growth by modified LDLs. Arterioscler Thromb 1993;13:331-7.  Back to cited text no. 201
    
202.
Hardwick SJ, Hegyi L, Clare K, Law NS, Carpenter KL, Mitchinson MJ, et al. Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein. J Pathol 1996;179:294-302.  Back to cited text no. 202
    
203.
Li LX, Chen JX, Liao DF, Yu L. Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro. Endothelium 1998;6:1-8.  Back to cited text no. 203
    
204.
Sata M, Walsh K. Oxidized LDL activates fas-mediated endothelial cell apoptosis. J Clin Invest 1998;102:1682-9.  Back to cited text no. 204
    
205.
Loidl A, Claus R, Ingolic E, Deigner HP, Hermetter A. Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells. Biochim Biophys Acta 2004;1690:150-8.  Back to cited text no. 205
    
206.
Galle J, Hansen-Hagge T, Wanner C, Seibold S. Impact of oxidized low density lipoprotein on vascular cells. Atherosclerosis 2006;185:219-26.  Back to cited text no. 206
    
207.
Lü Y, Liu JH, Zhang LK, DU J, Zeng XJ, Hao G, et al. Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells. Chin Med J (Engl) 2010;123:3417-21.  Back to cited text no. 207
    
208.
Shao M, Lu X, Cong W, Xing X, Tan Y, Li Y, et al. Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress. PLoS One 2014;9:e92574.  Back to cited text no. 208
    
209.
Shen Y, Ma X, Zhou J, Pan X, Hao Y, Zhou M, et al. Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 2013;12:124.  Back to cited text no. 209
    
210.
Kim WJ, Kim SS, Lee HC, Song SH, Bae MJ, Yi YS, et al. Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes. J Korean Med Sci 2015;30:586-90.  Back to cited text no. 210
    
211.
Lee Y, Lim S, Hong E, Kim J, Moon M, Chun E, et al. Serum FGF-21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol 2014;80:57-64.  Back to cited text no. 211
    
212.
Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: An update. Hypertension 2001;37:1053-9.  Back to cited text no. 212
    
213.
Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213-23.  Back to cited text no. 213
    
214.
Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: A brief review. Cardiovasc Toxicol 2001;1:181-93.  Back to cited text no. 214
    
215.
Boudina S, Abel ED. Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 2010;11:31-9.  Back to cited text no. 215
    
216.
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014;57:660-71.  Back to cited text no. 216
    
217.
Cai L, Kang YJ. Cell death and diabetic cardiomyopathy. Cardiovasc Toxicol 2003;3:219-28.  Back to cited text no. 217
    
218.
Acar E, Ural D, Bildirici U, Sahin T, Yılmaz I. Diabetic cardiomyopathy. Anadolu Kardiyol Derg 2011;11:732-7.  Back to cited text no. 218
    
219.
Zhang C, Huang Z, Gu J, Yan X, Lu X, Zhou S, et al. Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. Diabetologia 2015;58:1937-48.  Back to cited text no. 219
    
220.
Yan X, Chen J, Zhang C, Zhou S, Zhang Z, Chen J, et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J Cell Mol Med 2015;19:1557-68.  Back to cited text no. 220
    
221.
Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 1974;36:413-59.  Back to cited text no. 221
    
222.
Barry SP, Davidson SM, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 2008;40:2023-39.  Back to cited text no. 222
    
223.
Sales ML, Schreiber R, Ferreira-Sae MC, Fernandes MN, Piveta C, Cipolli JA, et al. The functional Toll-like receptor 4 Asp299Gly polymorphism is associated with lower left ventricular mass in hypertensive women. Clin Chim Acta 2010;411:744-8.  Back to cited text no. 223
    
224.
Yamamoto S, Kita S, Iyoda T, Yamada T, Iwamoto T. New molecular mechanisms for cardiovascular disease: Cardiac hypertrophy and cell-volume regulation. J Pharmacol Sci 2011;116:343-9.  Back to cited text no. 224
    
225.
Frohlich ED, Susic D. Pressure overload. Heart Fail Clin 2012;8:21-32.  Back to cited text no. 225
    
226.
Lovric J, Mano M, Zentilin L, Eulalio A, Zacchigna S, Giacca M. Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins. Mol Ther 2012;20:2087-97.  Back to cited text no. 226
    
227.
Shenje LT, Andersen P, Halushka MK, Lui C, Fernandez L, Collin GB, et al. Mutations in Alström protein impair terminal differentiation of cardiomyocytes. Nat Commun 2014;5:3416.  Back to cited text no. 227
    
228.
Grove D, Zak R, Nair KG, Aschenbrenner V. Biochemical correlates of cardiac hypertrophy. IV. Observations on the cellular organization of growth during myocardial hypertrophy in the rat. Circ Res 1969;25:473-85.  Back to cited text no. 228
    
229.
Simko F, Bednarova KR, Krajcirovicova K, Hrenak J, Celec P, Kamodyova N, et al. Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol-induced heart failure. J Pineal Res 2014;57:177-84.  Back to cited text no. 229
    
230.
Gupta PK, DiPette DJ, Supowit SC. Protective effect of resveratrol against pressure overload-induced heart failure. Food Sci Nutr 2014;2:218-29.  Back to cited text no. 230
    
231.
Heather LC, Catchpole AF, Stuckey DJ, Cole MA, Carr CA, Clarke K. Isoproterenol inducesin vivo functional and metabolic abnormalities: Similar to those found in the infarcted rat heart. J Physiol Pharmacol 2009;60:31-9.  Back to cited text no. 231
    
232.
Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M, et al. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res 2015;106:19-31.  Back to cited text no. 232
    
233.
Liu SQ, Tefft BJ, Roberts DT, Zhang LQ, Ren Y, Li YC, et al. Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. Am J Physiol Heart Circ Physiol 2012;303:H1446-58.  Back to cited text no. 233
    
234.
Liu SQ, Roberts D, Kharitonenkov A, Zhang B, Hanson SM, Li YC, et al. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep 2013;3:2767.  Back to cited text no. 234
    
235.
Cong WT, Ling J, Tian HS, Ling R, Wang Y, Huang BB, et al. Proteomic study on the protective mechanism of fibroblast growth factor 21 to ischemia-reperfusion injury. Can J Physiol Pharmacol 2013;91:973-84.  Back to cited text no. 235
    
236.
Hindricks J, Ebert T, Bachmann A, Kralisch S, Lössner U, Kratzsch J, et al. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol (Oxf) 2014;80:918-24.  Back to cited text no. 236
    
237.
Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine 2013;62:322-6.  Back to cited text no. 237
    
238.
Salehi M, Kamalidehghan B, Houshmand M, Aryani O, Sadeghizadeh M, Mossalaeie M. Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich ataxia). Mol Biol Rep 2013;40:6495-9.  Back to cited text no. 238
    
239.
Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 2013;81:1819-26.  Back to cited text no. 239
    
240.
Roesch SL, Styer AM, Wood GC, Kosak Z, Seiler J, Benotti P, et al. Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes. PLoS One 2015;10:e0116928.  Back to cited text no. 240
    
241.
Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) 2009;71:369-75.  Back to cited text no. 241
    
242.
Lin Y, Xiao YC, Zhu H, Xu QY, Qi L, Wang YB, et al. Serum fibroblast growth factor 21 levels are correlated with the severity of diabetic retinopathy. J Diabetes Res 2014;2014:929756.  Back to cited text no. 242
    
243.
Korwutthikulrangsri M, Mahachoklertwattana P, Chanprasertyothin S, Pongratanakul S, Poomthavorn P. Serum fibroblast growth factor 21 in overweight and obese Thai children and adolescents: Its relation to glucose metabolism and its change after glucose loading. Clin Endocrinol (Oxf) 2015;83:820-7.  Back to cited text no. 243
    
244.
Reinehr T, Karges B, Meissner T, Wiegand S, Fritsch M, Holl RW, et al. Fibroblast growth factor 21 and fetuin-a in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab 2015;100:3004-10.  Back to cited text no. 244
    
245.
Dostálová I, Kaválková P, Haluzíková D, Lacinová Z, Mráz M, Papezová H, et al. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab 2008;93:3627-32.  Back to cited text no. 245
    
246.
Durovcová V, Marek J, Hána V, Matoulek M, Zikán V, Haluzíková D, et al. Plasma concentrations of fibroblast growth factors 21 and 19 in patients with Cushing's syndrome. Physiol Res. 2010;59:415-22.  Back to cited text no. 246
    
247.
Hanssen MJ, Broeders E, Samms RJ, Vosselman MJ, van der Lans AA, Cheng CC, et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep 2015;5:10275.  Back to cited text no. 247
    
248.
Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 2010;53:934-40.  Back to cited text no. 248
    
249.
Alisi A, Ceccarelli S, Panera N, Prono F, Petrini S, De Stefanis C, et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS One 2013;8:e67160.  Back to cited text no. 249
    
250.
Kukla M, Berdowska A, Stygar D, Gabriel A, Mazur W, Łogiewa-Bazger B, et al. Serum FGF-21 and RBP4 levels in patients with chronic hepatitis C. Scand J Gastroenterol 2012;47:1037-47.  Back to cited text no. 250
    
251.
Gariani K, Drifte G, Dunn-Siegrist I, Pugin J, Jornayvaz FR. Increased FGF21 plasma levels in humans with sepsis and SIRS. Endocr Connect 2013;2:146-53.  Back to cited text no. 251
    
252.
Hulejová H, Andrés Cerezo L, Kuklová M, Pecha O, Vondráček T, Pavelka K, et al. Novel adipokine fibroblast growth factor 21 is increased in rheumatoid arthritis. Physiol Res 2012;61:489-94.  Back to cited text no. 252
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
   Abstract
  Introduction
   Intracellular Si...
   Physiological Ro...
   The Role of Seru...
  Conclusion
   References
   Article Figures

 Article Access Statistics
    Viewed541    
    Printed45    
    Emailed0    
    PDF Downloaded102    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]