Affinage

FGF19

Fibroblast growth factor 19 · UniProt O95750

Length
216 aa
Mass
24.0 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF19 is an intestine-derived endocrine hormone that coordinates postprandial hepatic metabolism by acting as a ligand for FGF receptors in partnership with the obligate co-receptor β-Klotho (KLB), with tissue-specific outputs dictated by which FGFR isoform is co-expressed with KLB (PMID:17623664, PMID:17627937). Signaling efficiently through FGFR4-KLB in liver and through FGFR1c/2c/3c-KLB in extrahepatic tissues, FGF19 partitions its activities along structurally separable receptor-binding determinants: residues governing FGFR4 engagement drive bile acid suppression and hepatocyte proliferation, while distinct determinants mediate FGFR1c-dependent metabolic regulation of glucose and lipid homeostasis (PMID:19706524, PMID:20018895, PMID:20660733, PMID:22457778). Through hepatic FGFR4 it represses CYP7A1-mediated bile acid synthesis (PMID:17627937), and it stimulates insulin-independent glycogen and protein synthesis via a MAPK pathway that activates glycogen synthase and the translation machinery (PMID:21436455). FGF19 reinforces bile acid and cholesterol homeostasis by activating Src to phosphorylate FXR at Y67, controlling FXR nuclear localization and its transcription of cholesterol-transport genes (PMID:29968724, PMID:30996006), and it directs cholesterol handling through SHP—both as a phospho-dependent SREBP-2 partner suppressing cholesterol biosynthesis (PMID:26634251) and through an LXR/ABCA1/MEK1 axis promoting HDL biogenesis and cholesterol efflux (PMID:30679232). FGF19 also enforces postprandial epigenetic repression of hepatic autophagy via an FGF19-SHP-LSD1 axis that demethylates H3K4 at autophagy gene promoters (PMID:28446510). Its pharmacologic weight-loss and glycemic effects are mediated through neuronal β-Klotho rather than liver or adipose tissue (PMID:28988823), and anti-obesity action is independent of UCP1 thermogenesis, reflecting reduced bile acid synthesis and dietary lipid absorption (PMID:31767164). Distinct from its metabolic roles, FGF19 is oncogenic in hepatocellular carcinoma through FGFR4-driven STAT3 activation that operates non-cell-autonomously via IL-6 from the liver microenvironment, an activity separable from bile acid regulation (PMID:24728076, PMID:28508871). FGF19 transcription is induced in the intestine by bile acid/nuclear-receptor inputs (FXR, PXR) and by ER stress via ATF4 (PMID:23205607, PMID:17696253, PMID:22561792), and it functions developmentally through FGFR4-MAPK signaling in eye and forebrain morphogenesis (PMID:17000708, PMID:15921496, PMID:16256099, PMID:18089288).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2007 High

    Established the receptor logic of FGF19 by showing that β-Klotho is the obligate co-receptor that licenses FGF19 binding and signaling, explaining how a circulating hormone achieves tissue-specific action.

    Evidence Cell-based signaling, receptor binding, and in vivo mouse injection with tissue-specific c-Fos/CYP7A1 readouts

    PMID:17623664 PMID:17627937

    Open questions at the time
    • Structural basis of the FGF19-KLB-FGFR4 ternary complex not resolved
    • Determinants of FGFR isoform selectivity not yet mapped
  2. 2009 High

    Dissected which receptor drives which output, showing FGFR4 engagement is responsible for bile acid suppression and hepatocyte proliferation while β-Klotho/FGFR1c mediates glucose regulation.

    Evidence C-terminal deletion mutant (FGF19dCTD), chimeric FGF19/FGF21 proteins, in vivo treatment in ob/ob mice with gene expression and proliferation readouts

    PMID:19706524 PMID:20018895

    Open questions at the time
    • Whether adipose versus other extrahepatic FGFR1c tissues carry the glucose effect not pinned down at this stage
  3. 2010 High

    Confirmed that mitogenic FGFR4 activity and metabolic activity are structurally separable, enabling design of non-mitogenic metabolic variants.

    Evidence Structure-guided mutagenesis with in vivo metabolic and proliferation assays in mice

    PMID:20660733

    Open questions at the time
    • Long-term safety of FGFR4-sparing variants not addressed
  4. 2011 High

    Defined how FGF19 maintains postprandial fuel homeostasis, showing it drives glycogen and protein synthesis via MAPK independently of insulin/Akt.

    Evidence In vivo isotope labeling, pathway inhibitors, FGF15-null mice, and streptozotocin-diabetic rescue

    PMID:21436455 PMID:21437243

    Open questions at the time
    • Receptor and effector linking MAPK to glycogen synthase not fully defined
  5. 2011 Medium

    Identified upstream transcriptional control of FGF19 by bile acids and xenobiotic sensing, including a pathological PXR-driven program in colon cancer.

    Evidence ChIP for PXR on FGF19 promoter, xenograft rescue, RNAi, and reporter assays; PXR/RXR LCA-responsive promoter mapping

    PMID:17696253 PMID:21747170

    Open questions at the time
    • Single-lab xenograft evidence
    • Relevance of tumor-specific FGF19 induction to human colon cancer not established
  6. 2012 Medium

    Quantified FGF19 versus FGF21 receptor preferences and engineered biased variants, confirming the βKlotho/FGFR1c complex is central to metabolic action.

    Evidence Quantitative binding kinetics, signaling assays, and in vivo metabolic phenotyping of FGF19-7 variant in DIO/ob/ob mice

    PMID:22442730 PMID:22457778

    Open questions at the time
    • Single-lab biased-variant data
    • Affinity measurements not tied to in-tissue receptor stoichiometry
  7. 2012 Medium

    Mapped the intestinal FXR-driven transcriptional activation of FGF19 and its negative regulation, defining feedback control of the bile acid circuit.

    Evidence Reporter assays, EMSA, ChIP, GST pull-down, and SREBP-2 overexpression in human intestinal cells

    PMID:22561792 PMID:24321096

    Open questions at the time
    • In vivo relevance of SREBP-2/FXR antagonism not tested
    • Single-lab promoter work
  8. 2013 Medium

    Linked ER stress to FGF19 induction via ATF4 binding an amino acid response element in the promoter, independent of FXR.

    Evidence Reporter deletion constructs, EMSA, ChIP, and ATF4 overexpression/shRNA in Caco-2 cells

    PMID:23205607

    Open questions at the time
    • Physiological/pathological context of stress-induced FGF19 not defined in vivo
  9. 2014 High

    Separated FGF19's oncogenic activity from its metabolic activity by showing HCC promotion proceeds through STAT3, an activity removable in the M70 variant.

    Evidence Engineered M70 variant, transgenic HCC mouse model, and STAT3 signaling/tumor growth assays

    PMID:24728076

    Open questions at the time
    • Mechanism connecting FGFR4 to STAT3 not resolved at this stage
  10. 2015 High

    Identified SHP as a phospho-dependent SREBP-2 partner downstream of FGF19 that represses cholesterol biosynthesis genes genome-wide.

    Evidence Liver ChIP-seq, Co-IP, SHP Thr-55 phospho-mutagenesis, and SHP-knockout mice with FGF19 treatment

    PMID:26634251

    Open questions at the time
    • Kinase phosphorylating SHP at Thr-55 not identified
    • Single rigorous study
  11. 2017 High

    Resolved the non-cell-autonomous basis of FGF19-driven HCC, showing FGF19 stimulates microenvironmental IL-6 that activates hepatocyte STAT3.

    Evidence Hepatocyte-specific Stat3 knockout, Il6 knockout, anti-IL-6 antibody, and JAK inhibitor in transgenic HCC mice

    PMID:28508871

    Open questions at the time
    • Cellular source of IL-6 and the FGF19 receptor on those cells not fully defined
  12. 2017 High

    Localized the pharmacologic weight-loss and glycemic effects of FGF19 to neuronal β-Klotho, redefining the relevant target tissue.

    Evidence Neuronal, hepatic, and adipose tissue-specific β-Klotho knockout mice with metabolic phenotyping

    PMID:28988823

    Open questions at the time
    • Specific neuronal populations and downstream circuits not identified
  13. 2017 High

    Defined a post-translational arm of bile acid homeostasis in which FGF19-activated Src phosphorylates FXR at Y67 to control its nuclear localization, and an epigenetic arm repressing hepatic autophagy via SHP-LSD1.

    Evidence Y67F-FXR phospho-mutagenesis, liver-specific viral expression, Src knockdown, bile acid feeding/cholestasis models; SHP-null, LSD1-knockdown, FGF15-null mice with ChIP and autophagy assays

    PMID:28446510 PMID:29968724

    Open questions at the time
    • How FGF19/FGFR4 signaling activates Src not detailed
    • Promoter selectivity of the SHP-LSD1 complex incompletely defined
  14. 2019 Medium

    Extended FGF19's lipid control to biliary cholesterol excretion (via Y67-phosphorylated FXR at Abcg5/8 and Scarb1) and to HDL biogenesis through an LXR/ABCA1/MEK1 axis.

    Evidence Hepatic FXR reconstitution with Y67F mutant, Src knockdown, apoE-/- atherosclerosis model, ChIP, efflux assays; constitutively active MEK1/STAT3 constructs and ABCA1/FGFR4 perturbation in db/db and Apoe-/- mice

    PMID:30679232 PMID:30996006

    Open questions at the time
    • Single-lab studies
    • Integration of MEK1 and FXR-phosphorylation arms not reconciled
  15. 2019 Medium

    Showed FGF19's anti-obesity action does not require UCP1 thermogenesis but reflects suppressed bile acid synthesis and reduced lipid absorption.

    Evidence UCP1 knockout mice with FGF19 treatment, calorimetry, bile acid and fecal energy analysis

    PMID:31767164

    Open questions at the time
    • Reconciliation with the neuronal β-Klotho mechanism not directly addressed
  16. 2023 Medium

    Expanded the FGF19/FGFR4 oncogenic program across tumor types through autocrine signaling, feedback loops, and immune-stromal remodeling.

    Evidence Orthotopic/xenograft HCC, PDAC, gallbladder and colorectal liver metastasis models with pathway inhibitors, knockouts, ChIP, Ca2+ imaging, and immune cell phenotyping

    PMID:26498355 PMID:27192118 PMID:28951455 PMID:33754043 PMID:34163030 PMID:36907560 PMID:36919699 PMID:37345586

    Open questions at the time
    • Each mechanism rests on single-lab evidence
    • Relative contribution of these parallel oncogenic arms in human tumors unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the divergent FGF19 outputs—hepatic metabolic, neuronal pharmacologic, and oncogenic STAT3/immune arms—are integrated at the level of receptor complex composition and downstream effector choice remains unresolved.
  • No structural model of context-dependent receptor complexes
  • Mechanism selecting MAPK versus STAT3 versus Src outputs not defined
  • Branch point between metabolic and oncogenic signaling not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
FGFR1FGFR4KLB

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 FGF19 requires β-Klotho (KLB) as a co-receptor to bind FGFR4 and signal in hepatocytes; tissue-specific co-expression of KLB with particular FGFR isoforms (especially FGFR4 in liver) determines the tissue-specific metabolic activities of FGF19. Both FGF19 and FGF21 can signal through FGFR1-3 bound by β-Klotho, but only FGF19 signals efficiently through FGFR4. Cell-based signaling assays, receptor binding studies, mouse in vivo injection experiments, gene expression analysis The Journal of biological chemistry High 17623664 17627937
2007 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression in hepatocytes. In mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1 only where both KLB and FGFR4 are co-expressed. In vivo mouse injection, gene expression analysis, receptor distribution mapping The Journal of biological chemistry High 17627937
2009 FGF19 can interact directly with FGFR4 in the absence of β-Klotho in a heparin-dependent manner, whereas activation of FGFRs 1c, 2c, or 3c is completely β-Klotho-dependent. An FGF19 C-terminal deletion mutant (FGF19dCTD) lacking the β-Klotho interaction domain selectively activates FGFR4 signaling in liver and suppresses CYP7A1 but fails to improve glucose homeostasis in ob/ob mice, implicating adipose FGFR signaling (via β-Klotho) in glucose regulation. Receptor binding assays, engineered FGF19 deletion mutant (FGF19dCTD), in vivo mouse treatment, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 19706524
2009 FGF19-induced hepatocyte proliferation is mediated specifically through FGFR4 activation. Amino acid residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation; an FGF19/FGF21 chimera carrying these residues gains hepatocyte mitogenic activity. C-terminal truncation mutants, FGF19/FGF21 chimeric molecules, in vivo hepatocyte proliferation assay The Journal of biological chemistry High 20018895
2010 FGF19 structural determinants governing FGFR4 interaction (mitogenic) are separable from those governing FGFR1c/2c/3c interaction (metabolic). FGF19 variants that lose FGFR4 activation retain metabolic activity (glucose lowering, insulin sensitivity) but lose hepatocyte proliferative activity in mice. Structure-guided mutagenesis of FGF19, in vivo metabolic and proliferation assays in mice Proceedings of the National Academy of Sciences of the United States of America High 20660733
2011 FGF19 stimulates hepatic protein synthesis and glycogen synthesis through a MAPK signaling pathway that activates components of the protein translation machinery and stimulates glycogen synthase activity, independently of insulin and Akt. Mice lacking FGF15 (mouse ortholog) fail to maintain postprandial blood glucose and liver glycogen; FGF19 treatment restored glycogen in insulin-deficient diabetic animals. In vivo isotope labeling for protein/glycogen synthesis, signaling pathway inhibitors, FGF15 knockout mice, streptozotocin-diabetic mouse model Science (New York, N.Y.) High 21436455
2011 FGF19 regulates bile acid biosynthesis (CYP7A1 suppression) and hepatocyte proliferation via FGFR4, but FGFR4 is not essential for FGF19 to improve glucose and lipid metabolism; an FGF19 variant (FGF19v) selectively impaired in FGFR4 activation retains metabolic activity in high-fat diet and ob/ob mice. Fgfr4-deficient mice, FGF19v variant protein, in vivo metabolic phenotyping, gene expression PloS one High 21437243
2011 Pregnane X receptor (PXR) activation drives colon tumor growth via tumor-specific induction of FGF19; PXR binds the FGF19 promoter in colon cancer cells and induces FGF19 transcription only in cancer (not normal) cells, and PXR-mediated tumor phenotypes (growth, invasion, metastasis) require FGF19 signaling. Xenograft tumor model, ChIP assay (PXR binding to FGF19 promoter), RNAi knockdown, reporter assay The Journal of clinical investigation Medium 21747170
2012 FGF21 binds FGFR1-KLB with much higher affinity than FGFR4-KLB, whereas FGF19 binds both FGFR1-KLB and FGFR4-KLB with comparable affinity. KLB is an indispensable mediator for FGF19 and FGF21 binding to FGFRs; FGF1 binds FGFRs independently of KLB and cannot displace FGF19/FGF21, and vice versa. Quantitative binding kinetics assays, downstream signal transduction assays, in vivo early response gene measurements in mice PloS one Medium 22442730
2012 A biased FGF19 variant (FGF19-7) with strong preference for FGFR1c over FGFR4 is equally efficacious as wild-type FGF19 in regulating glucose, lipid, and energy metabolism in DIO and ob/ob mice, demonstrating that the βKlotho/FGFR1c receptor complex is central to the metabolic functions of endocrine FGFs. Engineered FGF19 receptor-specificity variant, in vivo metabolic phenotyping in multiple mouse models PloS one Medium 22457778
2014 FGF19 promotes hepatocellular carcinoma (HCC) by activating the STAT3 pathway, an activity separable from its bile acid regulatory activity. An engineered FGF19 variant (M70) fully retains bile acid regulatory activity but does not activate STAT3 and does not promote HCC formation in mice; M70 also inhibits FGF19-dependent tumor growth. Engineered FGF19 variant (M70), transgenic mouse HCC model, STAT3 signaling assays, in vivo tumor growth assays Cancer research High 24728076
2017 FGF19-driven hepatocarcinogenesis operates through a non-cell-autonomous mechanism: FGF19 stimulates IL-6 production in the liver microenvironment, which then activates STAT3 in hepatocytes. Hepatocyte-specific Stat3 deletion, Il6 ablation, anti-IL-6 antibody, or JAK inhibitor each abolish FGF19-induced tumorigenesis while leaving bile acid, glucose, and energy metabolic functions intact. Hepatocyte-specific Stat3 knockout, Il6 knockout mice, neutralizing anti-IL-6 antibody, JAK inhibitor, FGF19 transgenic mouse HCC model Nature communications High 28508871
2017 The pharmacologic weight-loss and glycemic effects of FGF19 (and FGF21) are mediated through the nervous system via β-Klotho in neurons, not via liver or adipose tissue. Neuronal-specific β-Klotho knockout abolishes FGF19-induced weight loss and glucose/insulin lowering, demonstrating the central nervous system as the primary mediator of these pharmacologic effects. Tissue-specific β-Klotho knockout mice (neuronal, hepatic, adipose), metabolic phenotyping Cell metabolism High 28988823
2017 Postprandial FGF19 signaling activates Src kinase, which phosphorylates FXR at Y67 in hepatocytes. This phosphorylation is critical for FXR nuclear localization and transcriptional regulation of bile acid homeostasis. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation impairs homeostatic responses to bile acid feeding and exacerbates cholestatic pathologies. Phospho-site mutagenesis (Y67F-FXR), liver-specific viral expression, Src knockdown mice, bile acid feeding challenge, cholestatic drug model Nature communications High 29968724
2017 FGF19 mediates postprandial epigenetic repression of hepatic autophagy through the FGF19-SHP-LSD1 axis: FGF19 signals to recruit Small Heterodimer Partner (SHP), which recruits histone demethylase LSD1 to CREB-bound autophagy gene promoters (including Tfeb), leading to demethylation of H3K4-me2/3 and repression of autophagy including lipophagy. FGF15-null mice show attenuated feeding-mediated autophagy inhibition. SHP-null mice, LSD1 knockdown mice, FGF15-null mice, ChIP assays, histone modification analysis, macroautophagy assays The EMBO journal High 28446510
2015 FGF19-stimulated SHP (Small Heterodimer Partner) is a global transcriptional partner of SREBP-2 in the liver. FGF19 increases functional interaction between endogenous SHP and SREBP-2, inhibiting SREBP-2 target genes involved in cholesterol biosynthesis. FGF19-induced phosphorylation of SHP at Thr-55 is required for its interaction with SREBP-2 and reduction of liver/serum cholesterol. Liver ChIP-seq (genome-wide SHP binding), Co-immunoprecipitation, SHP phospho-site mutagenesis, SHP-knockout mice, FGF19 treatment Genome biology High 26634251
2019 FGF19/FGF15 signaling-activated Src phosphorylates hepatic FXR at Y67, which upregulates cholesterol transport genes (Scarb1, Abcg5/8) for biliary cholesterol excretion. Phospho-defective Y67F-FXR substitution blunts cholesterol-lowering, and Src knockdown impairs cholesterol regulation. FGF19 treatment increases FXR occupancy at Abcg5/8 and Scarb1 loci and promotes cholesterol efflux; these effects are abolished by Y67F-FXR or Src inhibition. Hepatic FXR knockout/knockdown reconstitution with Y67F mutant, Src knockdown, apoE-deficient atherosclerosis model, ChIP, cholesterol efflux assay, FGF19 treatment The Journal of biological chemistry High 30996006
2016 FGF19 promotes epithelial-mesenchymal transition (EMT) in HCC cells via the FGFR4/GSK3β/β-catenin axis: FGF19 represses E-cadherin, and EMT induced by FGF19 is blocked by GSK3β inhibitor pretreatment or FGFR4 knockout, implicating GSK3β as a required intermediary. FGF19 overexpression/knockdown, FGFR4 CRISPR knockout, GSK3β inhibitor treatment, EMT marker analysis, invasion assays Oncotarget Medium 26498355
2017 FGF19 protects HCC cells against endoplasmic reticulum stress-induced apoptosis through the FGFR4-GSK3β-Nrf2 signaling cascade, promoting nuclear accumulation of Nrf2. FGF19 expression in stressed cells is induced by ATF4, which directly binds the FGF19 promoter. ER stress induction in HCC cells, FGF19 overexpression/silencing, mouse xenograft model, signaling pathway analysis Cancer research Medium 28951455
2013 ATF4 (activating transcription factor 4), activated in response to ER stress, directly binds an amino acid response element (AARE) in the FGF19 promoter and induces FGF19 transcription in intestinal cells independently of farnesoid X receptor. Thapsigargin-induced ER stress markedly increases FGF19 mRNA and secreted protein in Caco-2 cells; shRNA depletion of ATF4 attenuates this induction. Reporter gene assay with promoter deletion constructs, EMSA, ChIP assay, ATF4 overexpression/shRNA knockdown The Biochemical journal Medium 23205607
2007 FGF19 expression in intestinal cells is induced by lithocholic acid (LCA) via the pregnane X receptor (PXR). PXR/RXR overexpression with LCA or rifampicin stimulation drives FGF19 promoter activity, and the LCA-responsive element maps to a proximal region with two PXR binding half-sites. Reporter gene assay with FGF19 promoter deletion constructs, PXR/RXR co-transfection, qRT-PCR in LS174T intestinal cells World journal of gastroenterology Medium 17696253
2012 FXR transcriptionally activates FGF19 through multiple responsive elements in the FGF19 promoter and gene body (at -1866 to -1833, -1427 to -1353, and -75 to +262 relative to the transcription start), where FXR/RXRα heterodimers bind IR1, ER2, and DR8 motifs as confirmed by EMSA and ChIP assay. Reporter assay with multiple FGF19 promoter deletion constructs, EMSA, ChIP assay, mutagenesis of nuclear receptor binding motifs The Journal of steroid biochemistry and molecular biology Medium 22561792
2013 SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells by interacting directly with FXR and attenuating FXR/RXRα binding to the IR-1 motif in the FGF19 gene, without itself binding the IR-1 motif. GST pull-down confirmed direct SREBP-2/FXR protein interaction. Reporter gene assay, EMSA, ChIP assay, GST pull-down, overexpression of constitutively active SREBP-2, site mutagenesis Biochemical and biophysical research communications Medium 24321096
2006 FOXC1 transcription factor directly regulates FGF19 expression in corneal and periocular mesenchymal cells. FGF19 signals through FGFR4 tyrosine kinase to promote MAPK phosphorylation in the cornea. Loss of either FOXC1 or FGF19 causes complementary anterior segment dysgeneses. Chromatin enrichment assay, cell culture overexpression, zebrafish embryo loss-of-function, MAPK phosphorylation assays Human molecular genetics Medium 17000708
2005 In the chick embryo, FGF19 is expressed in the distal optic vesicle and signals through FGFR4 to participate in lens induction in collaboration with FGF8-L-Maf signaling. Inhibition of FGF19 signal via a secreted FGFR4 decoy induces L-Maf expression; L-Maf misexpression ectopically induces Fgf19; FGF8 induces Fgf19 in addition to L-Maf. Misexpression (gain-of-function) and secreted dominant-negative FGFR4 (loss-of-function) in chick embryo, gene expression analysis Development, growth & differentiation Medium 15921496
2005 In zebrafish, Fgf19 is required for forebrain development: Fgf19 knockdown reduces cell proliferation and survival in the embryonic brain, impairs development of the ventral telencephalon and diencephalon, and disrupts specification of GABAergic interneurons and oligodendrocytes. Fgf19 expression is downstream of Hedgehog (Hh) signaling, and Fgf19 overexpression partially rescues the forebrain phenotype caused by Hh inhibition. Morpholino knockdown of Fgf19 in zebrafish, Hh pathway inhibition, Fgf19 overexpression rescue experiment Developmental biology Medium 16256099
2007 In zebrafish, Fgf19 expressed in the nasal retina and lens is required for lens fiber cell differentiation, cell survival (but not proliferation) in the lens and retina, and nasal-temporal patterning of the retina critical for retinal ganglion cell axon guidance. Loss of Fgf19 causes size reduction of lens and retina, failure of choroid fissure closure, and aberrant axon pathfinding. Morpholino knockdown of Fgf19, Fgf19 overexpression, eye transplantation in zebrafish, marker gene analysis Developmental biology Medium 18089288
2016 In breast cancer cells co-expressing FGFR4 and FGF19, FGF19 acts as an autocrine ligand that activates FGFR4 to promote survival predominantly via PI3K/AKT signaling. siRNA silencing of FGF19 or neutralizing anti-FGF19 antibody decreases AKT phosphorylation and suppresses cancer cell growth and doxorubicin resistance specifically in FGFR4+/FGF19+ cells. siRNA knockdown, neutralizing antibody, AKT phosphorylation assays, cell viability assays in breast cancer cell lines Oncotarget Medium 27192118
2018 Molecular elements in the C-terminus of FGF19 are critical for KLB binding and receptor signaling. Short C-terminal FGF19 peptides competitively inhibit FGF19 activity via KLB binding. A single C-terminal amino acid in FGF19 modulates relative activity through FGFR1 versus FGFR4. The C-terminal sequence of FGF19 is structurally conserved for KLB binding despite sequence differences from FGF21. C-terminal peptide competition assays, alanine scanning mutagenesis, in vitro KLB-mediated signaling assays, in vivo obese mouse metabolic studies Molecular metabolism Medium 29789271
2015 IL-1β inhibits β-Klotho expression in hepatocytes via the JNK and NF-κB pathways, thereby impairing FGF19-induced ERK1/2 activation and cell proliferation. LPS inhibits β-Klotho and FGFR4 expression in mouse liver in vivo, but acts via IL-1β (not TNFα or IL-6) to inhibit β-Klotho transcription in liver cells. LPS treatment in vivo, cytokine treatment of hepatocyte cell lines, pathway inhibitors (JNK, NF-κB), FGF19 signaling readout (ERK1/2 phosphorylation), cell proliferation assay American journal of physiology. Endocrinology and metabolism Medium 26670488
2019 FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux by selectively modulating LXR signaling in the liver; ABCA1 and FGFR4 are identified as mediators. A constitutively active MEK1 (but not constitutively active STAT3) mimics FGF19/NGM282 effects on cholesterol, placing MEK1 downstream of FGF19 in cholesterol regulation. In vivo treatment of db/db and Apoe-/- mice, constitutively active MEK1/STAT3 constructs, ABCA1 and FGFR4 perturbation, cholesterol efflux assays, clinical trial measurement of HDL-C Journal of lipid research Medium 30679232
2021 FGF19/FGFR4 signaling promotes liver cancer stem cell (LCSC) self-renewal via activation of store-operated Ca2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. SOCE-calcineurin signaling then activates and induces nuclear translocation of NFATc2, which transcriptionally activates stemness genes (NANOG, OCT4, SOX2) as well as FGF19 itself, creating a positive feedback loop. FGF19 overexpression/silencing, FGFR4 activation/inhibition, Ca2+ imaging, sphere formation and clonogenicity assays, loss-of-function studies Theranostics Medium 33754043
2023 FGF19/FGFR4 signaling elevates ETV4 expression through ERK1/2 in HCC cells; ETV4 in turn upregulates FGFR4, creating a positive feedback loop. ETV4 transactivates PD-L1 and CCL2, promoting TAM and MDSC infiltration and suppressing CD8+ T cells to facilitate HCC metastasis. CCR2 inhibition or CCL2 knockdown impairs ETV4-induced immune cell infiltration. Orthotopic HCC mouse models, lentiviral overexpression/knockdown, flow cytometry, immunofluorescence, clodronate liposome macrophage depletion, CCR2 inhibitor treatment Journal of hepatology Medium 36907560
2023 In colorectal cancer liver metastasis (CRLM), FGF19 induces polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the FGFR4-JAK2-STAT3 pathway and an autocrine IL-1α loop. FGF19-induced iCAFs promote neutrophil extracellular trap (NET) formation via complement C5a and IL-1β, facilitating CRC liver colonization. In vivo liver metastasis models, FGFR4 pathway inhibition (fisogatinib), GPBAR1 knockout mice, GBC cell line experiments Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37345586
2021 In gallbladder carcinoma, bile acids upregulate FGF19 and FGFR4 co-expression by activating the GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promotes GBC progression via autocrine FGFR4 activation and downstream ERK signaling. GBC cell line experiments, GPBAR1 knockout mice, human patient samples (serum/bile), FGFR4 inhibitor treatment, transcription factor analysis Oncogene Medium 34163030
2023 HMGA1 chromatin regulator directly induces FGF19 expression by recruiting active histone marks (H3K4me3, H3K27Ac) to the FGF19 gene locus. FGF19 disruption (gene silencing or FGFR4 inhibitor BLU9931) recapitulates most phenotypes of HMGA1 deficiency — decreased tumor growth and desmoplastic stroma formation — in PDAC mouse models. RNA sequencing, ChIP for active histone marks, FGF19 gene silencing, FGFR4 inhibitor treatment, KPC mouse model, subcutaneous/orthotopic PDAC models The Journal of clinical investigation Medium 36919699
2019 The anti-obesity effect of FGF19 in mice does not require UCP1-dependent thermogenesis; FGF19-induced weight loss in UCP1 knockout mice is associated with inhibition of bile acid synthesis and reduction of dietary lipid absorption (increased fecal energy content, reduced hepatic bile acid species), rather than increased caloric expenditure. UCP1 knockout mice, FGF19 treatment, calorimetry, bile acid analysis, fecal energy content measurement, gene expression Molecular metabolism Medium 31767164

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. The Journal of biological chemistry 651 17623664
2011 FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science (New York, N.Y.) 515 21436455
2011 Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening. Cancer cell 373 21397858
2014 Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology (Baltimore, Md.) 342 24798001
2007 Liver-specific activities of FGF19 require Klotho beta. The Journal of biological chemistry 236 17627937
2017 FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell metabolism 226 28988823
2007 Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 223 17599042
2014 Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. International journal of obesity (2005) 177 24813368
2018 Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. Journal of hepatology 176 29654817
2023 FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. Journal of hepatology 175 36907560
2014 Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19. Cancer research 159 24728076
2011 FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PloS one 156 21437243
2009 FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. The Journal of biological chemistry 156 20018895
2007 Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nature genetics 156 17906623
2012 Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PloS one 154 22442730
2017 FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. Journal of experimental & clinical cancer research : CR 150 28069043
2014 A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Science translational medicine 141 25080475
2023 Gut microbiota-bile acid crosstalk regulates murine lipid metabolism via the intestinal FXR-FGF19 axis in diet-induced humanized dyslipidemia. Microbiome 132 38001551
2019 FGF19-FGFR4 Signaling in Hepatocellular Carcinoma. Cells 127 31167419
2010 Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proceedings of the National Academy of Sciences of the United States of America 125 20080590
2011 Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice. The Journal of clinical investigation 122 21747170
2017 H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma. Cancer research 118 29247039
2003 Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. International journal of molecular medicine 116 12792807
2004 Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction. Developmental biology 115 15081372
2011 Roles of FGF19 in liver metabolism. Cold Spring Harbor symposia on quantitative biology 112 21813638
2017 Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nature communications 109 28508871
2007 Actions and mode of actions of FGF19 subfamily members. Endocrine journal 104 17878606
2012 Fundamentals of FGF19 & FGF21 action in vitro and in vivo. PloS one 103 22675463
2021 FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway. Journal of cellular and molecular medicine 92 33751819
2016 FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation. Oncotarget 91 26498355
2010 Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19). Proceedings of the National Academy of Sciences of the United States of America 91 20660733
2018 Divergent effects of resistance and endurance exercise on plasma bile acids, FGF19, and FGF21 in humans. JCI insight 90 30089729
2014 Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nature reviews. Gastroenterology & hepatology 88 24662279
2017 Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. Journal of hepatology 85 28189755
2023 FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 84 37345586
2020 FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human. Frontiers in endocrinology 78 33414764
2009 Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice. Proceedings of the National Academy of Sciences of the United States of America 78 19706524
2020 Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression. Frontiers in cell and developmental biology 74 32154250
2020 The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH. Hepatology (Baltimore, Md.) 74 32794259
2017 FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4-GSK3β-Nrf2 Signaling. Cancer research 73 28951455
2012 FGF19 and cancer. Advances in experimental medicine and biology 73 22396170
2016 Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival. Oncotarget 71 27192118
2005 Fgf19 regulated by Hh signaling is required for zebrafish forebrain development. Developmental biology 69 16256099
2018 FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma. Oncogene 67 30518874
2020 FGF19 and FGF21: In NASH we trust. Molecular metabolism 66 33383173
2019 Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development. Hepatology (Baltimore, Md.) 66 31206730
2017 A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy. The EMBO journal 65 28446510
2015 Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma. Diseases (Basel, Switzerland) 64 28943626
2020 ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 63 33288659
2018 Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. Nature communications 63 29968724
2016 Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea. The American journal of gastroenterology 55 26856750
2007 Fgf19 is required for zebrafish lens and retina development. Developmental biology 53 18089288
2021 FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis. Oncogene 50 34163030
2018 FGFR4 provides the conduit to facilitate FGF19 signaling in breast cancer progression. Molecular carcinogenesis 48 30074276
2017 Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis. PloS one 48 28570655
2007 Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. World journal of gastroenterology 48 17696253
2020 Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma. Cancers 47 31991869
2020 Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling. Cancer letters 46 33249195
2019 Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis. Handbook of experimental pharmacology 46 31201553
2014 Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations. Liver international : official journal of the International Association for the Study of the Liver 45 24393342
2023 Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho. Frontiers in endocrinology 44 37260446
2018 Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis. Scientific reports 44 30464200
2023 HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. The Journal of clinical investigation 43 36919699
2019 Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia. Obesity surgery 43 30976983
2015 FGF19 promotes progression of prostate cancer. The Prostate 43 25854696
2021 S100A16 promotes metastasis and progression of pancreatic cancer through FGF19-mediated AKT and ERK1/2 pathways. Cell biology and toxicology 42 33389337
2012 Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism. PloS one 40 22457778
2021 FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells. Theranostics 39 33754043
2020 Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH. American journal of physiology. Gastrointestinal and liver physiology 39 32003601
2018 Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity. Molecular metabolism 39 29789271
2018 Interaction of glucocorticoids with FXR/FGF19/FGF21-mediated ileum-liver crosstalk. Biochimica et biophysica acta. Molecular basis of disease 39 29883717
2006 FGF19 is a target for FOXC1 regulation in ciliary body-derived cells. Human molecular genetics 39 17000708
2015 IL-1β inhibits β-Klotho expression and FGF19 signaling in hepatocytes. American journal of physiology. Endocrinology and metabolism 38 26670488
2019 Phosphorylation of hepatic farnesoid X receptor by FGF19 signaling-activated Src maintains cholesterol levels and protects from atherosclerosis. The Journal of biological chemistry 37 30996006
2016 Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment. Oncotarget 37 27384874
2014 Soluble expression of disulfide bond containing proteins FGF15 and FGF19 in the cytoplasm of Escherichia coli. PloS one 37 24465767
2013 Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. The Journal of clinical endocrinology and metabolism 37 24297792
2024 Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. Journal of internal medicine 36 38212977
2023 FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway. Cell communication and signaling : CCS 36 36915160
2019 LncRNA SNHG16 promotes cell proliferation through miR-302a-3p/FGF19 axis in hepatocellular carcinoma. Neoplasma 36 30784284
2007 Expression of chick Fgf19 and mouse Fgf15 orthologs is regulated in the developing brain by Fgf8 and Shh. Developmental dynamics : an official publication of the American Association of Anatomists 35 17654705
2023 Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia. Hepatology (Baltimore, Md.) 34 36692476
2017 Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation. PloS one 34 28178326
2023 FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. Theranostics 33 36923538
2021 The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma. Scientific reports 33 33674622
2015 Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2. Genome biology 33 26634251
2020 Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104. Oncogene 32 32111983
2019 Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis. Journal of lipid research 31 30679232
2022 The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling. Frontiers in endocrinology 30 35116006
2018 IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 30 30279125
2019 The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis. Molecular metabolism 29 31767164
2013 SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells. Biochemical and biophysical research communications 29 24321096
2012 Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19. The Journal of steroid biochemistry and molecular biology 29 22561792
2005 Expression of Fgf19 in the developing chick eye. Brain research. Developmental brain research 27 15862633
2005 FGF19-FGFR4 signaling elaborates lens induction with the FGF8-L-Maf cascade in the chick embryo. Development, growth & differentiation 27 15921496
2023 Adipose-derived stem cell/FGF19-loaded microfluidic hydrogel microspheres for synergistic restoration of critical ischemic limb. Bioactive materials 25 37122899
2021 FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis. Journal of experimental & clinical cancer research : CR 25 33691750
2017 Dynamics of Bile Acid Profiles, GLP-1, and FGF19 After Laparoscopic Gastric Banding. The Journal of clinical endocrinology and metabolism 25 28591793
2017 FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas. Thoracic cancer 25 28906590
2013 FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to endoplasmic reticulum stress. The Biochemical journal 25 23205607

Missed literature

Know a paper Affinage missed for FGF19? Flag it for the maintainers and the community.

No submissions yet.