FGF 19 Human

What are the normal serum concentration ranges of FGF19 in healthy humans?

Normal serum FGF19 levels in apparently healthy individuals show considerable variation. According to quantitative ELISA measurements:

How does FGF19 expression differ from FGF21, and what are their primary physiological roles?

FGF19 and FGF21 are endocrine FGFs with distinct expression patterns and physiological roles:

• FGF19: Primarily expressed in intestinal enterocytes in response to bile acids via FXR activation. Shows diurnal rhythm with major peaks at 3 and 9 pm. Primarily regulates bile acid synthesis and has metabolic effects on glucose homeostasis .

• FGF21: Expressed mainly in the liver in response to fasting, protein restriction, and various metabolic stressors. Regulates energy homeostasis, glucose metabolism, and lipid metabolism .
  Key differences include:

• FGF19 is approximately 1000-fold more potent than FGF21 in inhibiting CYP7A1 mRNA expression in primary human hepatocytes .

• While both can activate FGFR1c/KLB, FGF19 also strongly activates FGFR4/KLB complexes .

• FGF19 increases plasma triglycerides and cholesterol in mice, whereas FGF21 decreases these parameters .

What receptor complexes does FGF19 bind to and activate?

FGF19 binds and activates specific receptor complexes:

• FGFR4/KLB complex: Primary receptor complex for FGF19's effects on bile acid metabolism. FGF19 is a potent activator of both mouse and human FGFR4/KLB complexes .

• FGFR1c/KLB complex: FGF19 activates this receptor complex but with lower potency than FGF21. It binds FGFR1c/mouse KLB with approximately 25-fold higher potency than FGFR1c/human KLB .
  These differential binding patterns explain the overlapping but distinct physiological effects of FGF19 and FGF21. The FGFR4-mediated effects of FGF19 are responsible for bile acid regulation and potentially its proliferative effects in the liver .

How is hepatic expression of FGF19 altered in cholestatic liver diseases?

In contrast to normal physiology where the ileum was traditionally considered the primary source of FGF19, research has revealed significant hepatic expression in cholestatic conditions:

• In Primary Biliary Cirrhosis (PBC), hepatic FGF19 mRNA expression is significantly increased compared to controls (9-fold increase, p=0.01) .

• Hepatic FGF19 expression correlates with fibrosis stage at liver biopsy in non-cirrhotic PBC patients .

• Increased hepatic FGF19 expression correlates with cholestatic parameters:

  • Alkaline phosphatase (ALP): Rho=0.469, p=0.03

  • Bilirubin: Rho=0.561, p=0.007

  • Mayo Risk Score for PBC: r=0.610, p=0.002
    These findings challenge the traditional understanding that FGF19 is produced exclusively in the ileum and suggest that hepatic FGF19 expression represents a compensatory mechanism in response to cholestasis .

What methodological approaches are most effective for measuring FGF19 in human research samples?

For quantitative assessment of human FGF19:

• ELISA-based methods: The most widely used approach is solid-phase ELISA, which can measure FGF19 in serum, plasma, and cell culture supernatants. The Quantikine Human FGF-19 Immunoassay is a validated 4.5-hour ELISA with:

  • Detection range: Accurately quantifies recombinant human FGF19 and naturally occurring FGF19

  • Precision: Intra-assay CV% of 3.6-6.4% and inter-assay CV% of 4.5-5.5%

  • Sample compatibility: Validated for serum, EDTA plasma, heparin plasma, and cell culture supernatants

• Tissue expression analysis:

  • qRT-PCR for FGF19 mRNA quantification in liver tissue samples

  • Immunohistochemistry for protein detection and localization
    When analyzing FGF19 in clinical studies, researchers should consider the diurnal variation of FGF19 (peaks at 3 and 9 pm) when designing sampling protocols .

How does FGF19 correlate with clinical parameters and disease severity in liver diseases?

Research indicates significant correlations between FGF19 levels and clinical parameters:
In Primary Biliary Cirrhosis (PBC):

• Serum FGF19 correlates with:

  • Hemoglobin (r=-0.394, p=0.01)

  • Albumin (r=-0.408, p=0.007)

  • Total bilirubin (r=0.577, p<0.0001)

  • AST (r=0.328, p=0.03)

  • Mayo Risk Score for PBC (r=0.514, p=0.0004)

• Hepatic FGF19 mRNA expression correlates with:

  • Fibrosis stage at liver biopsy

  • Cholestatic parameters (ALP: Rho=0.469, p=0.03; bilirubin: Rho=0.561, p=0.007)

  • Mayo Risk Score (r=0.610, p=0.002)
    In NAFLD/NASH:

• Serum FGF19 levels are reduced in individuals with overweight, obesity, and NAFLD compared to healthy controls

• Hepatic response to FGF19 appears to be impaired in humans with NAFLD

• Decreased FGF19 levels may contribute to NASH progression due to accumulation of toxic bile acids
  These correlations suggest FGF19 as a potential biomarker for disease severity in cholestatic liver diseases.

What is the evidence for FGF19's role in hepatocellular carcinoma and its potential as a therapeutic target?

FGF19 has been implicated as a driver in hepatocellular carcinoma (HCC):

How do FGF19 and bile acid metabolism interact, and what are the implications for experimental design?

FGF19 and bile acid metabolism form a complex regulatory network:

• Bile acid-induced FGF19 expression:

  • Bile acids activate FXR in intestinal enterocytes, stimulating FGF19 expression

  • FGF19 correlates with total bile acid concentration and specific bile acid species, particularly with:

    • Glycine and taurine conjugates of cholic acid (CA), chenodeoxycholic acid (CDCA), and ursodeoxycholic acid (UDCA)

    • 3-O-glucuronide conjugates of CDCA and lithocholic acid (LCA)

• FGF19 inhibition of bile acid synthesis:

  • FGF19 potently suppresses CYP7A1 expression via FGFR4/KLB signaling

  • This creates a negative feedback loop controlling bile acid homeostasis

• Experimental design implications:

  • When studying FGF19, researchers should measure relevant bile acid species

  • UDCA treatment affects FGF19 levels: FGF19 levels were significantly lower in UDCA responders than in UDCA non-responders (67.5±42.9 vs. 167.0±240.3 pg/ml; p=0.04)

  • Loss of KLB function (a co-receptor for FGF19) has been associated with bile acid diarrhea, suggesting the importance of evaluating gut symptoms in studies of FGF19 function
    Understanding these interactions is crucial when designing experiments to study either FGF19 or bile acid metabolism.

What are the key considerations when developing or utilizing FGF19 analogues for research?

When developing or working with FGF19 analogues, several critical factors must be considered:

• Receptor selectivity:

  • FGF19 activates both FGFR4/KLB (mediating bile acid effects) and FGFR1c/KLB (mediating metabolic effects)

  • Selective engineering can separate these functions, which is crucial for therapeutic development

• Mitogenic potential:

  • FGF19 has demonstrated proliferative effects in liver tissue, raising concerns about potential carcinogenicity

  • Published data indicate that FGF19 can induce proliferation in liver tissue

  • Modified FGF19 analogues have been developed that retain metabolic benefits while eliminating tumorigenic potential

• Species differences:

  • FGF19 binds mouse KLB with higher affinity than human KLB

  • FGF19 is approximately 25-fold more potent at FGFR1c/mouse KLB compared to FGFR1c/human KLB

  • These species differences must be considered when translating findings from mouse models to humans

• Assessment of activity:

  • Monitoring CYP7A1 expression provides a direct measure of FGF19 activity on bile acid metabolism

  • For proliferative potential, Ki-67 labeling index in liver tissue can be used

How should researchers design studies to evaluate FGF19 in the context of NASH treatment?

When designing studies to evaluate FGF19 for NASH treatment:

• Patient selection considerations:

  • Baseline FGF19 levels are reduced in individuals with NAFLD/NASH

  • Hepatic response to FGF19 may be impaired in NAFLD patients

  • Genetic variations in KLB (rs17618244) have been associated with increased risk of ballooning and lobular inflammation in children with NAFLD

• Biomarker assessment:

  • Measure baseline and treatment-induced changes in:

    • Serum FGF19 levels

    • Bile acid composition and concentration

    • Liver enzymes and markers of cholestasis

    • Histological assessment of steatosis, inflammation, and fibrosis

• Safety monitoring:

  • Monitor for potential mitogenic effects using appropriate biomarkers

  • Use modified FGF19 analogues with reduced proliferative potential

  • Consider dual FGF19/FGF21 approaches that may provide complementary benefits

• Comparative approach:

  • FGF19 and FGF21 analogues both show promise for NASH treatment through different mechanisms

  • Consider evaluating both in parallel to determine optimal therapeutic approach
    Current phase 2 clinical trials with FGF19 analogues have shown promising results for NASH resolution and decrease in fibrosis .

What quality control parameters should be considered when measuring FGF19 in research samples?

For reliable FGF19 measurement, researchers should consider:

• Assay validation parameters:

  • Precision: Based on validated ELISA data, acceptable intra-assay CV% should be <6.4% and inter-assay CV% <5.5%

  • Sensitivity: Ensure assay can detect the expected range (approximately 30-550 pg/mL in healthy subjects)

  • Specificity: Validate that the assay distinguishes FGF19 from related proteins like FGF21

• Sample handling:

  • Consider diurnal variation: FGF19 shows a diurnal rhythm with two major peaks at 3 and 9 pm

  • Sample type consistency: Similar but not identical values are observed in serum (mean 189 pg/mL), EDTA plasma (179 pg/mL), and heparin plasma (183 pg/mL)

• Experimental variables affecting FGF19 levels:

  • Fasting/feeding status: FGF19 is regulated by bile acid flux which is affected by meals

  • UDCA treatment status: UDCA responders show significantly different FGF19 levels than non-responders

  • Presence of cholestasis: Significantly alters both circulating and hepatic FGF19 levels

• Reference standards:

  • Use recombinant human FGF19 as standard

  • Validated ELISA kits have shown parallel curves between recombinant and naturally occurring human FGF19

How can researchers differentiate between the metabolic and proliferative effects of FGF19 in experimental models?

To distinguish between FGF19's metabolic and proliferative effects:

• Receptor-selective variants:

  • FGFR4/KLB-selective FGF19 variants (such as FGF19dCTD) retain bile acid-lowering effects while also affecting plasma lipids

  • These selective variants can help delineate pathway-specific effects

• Tissue-specific knockout models:

  • Liver-specific FGFR4-deficient mice can be used to evaluate FGFR4-independent effects of FGF19

  • These models help determine if observed effects require FGFR4 signaling

• Proliferation assessment methods:

  • Ki-67 labeling index in liver tissue is a standard method to assess proliferative potential

  • When testing FGF19 variants, use known FGF19 samples (in FGFR4-expressing mice) as positive controls

• Metabolic assessment methods:

  • CYP7A1 expression for bile acid effects

  • Glucose tolerance tests for glycemic effects

  • Lipid profiling for effects on cholesterol and triglycerides

  • Energy expenditure measurements for metabolic rate effects
    These approaches allow researchers to develop or test FGF19-based therapeutics that retain beneficial metabolic effects while minimizing proliferative potential.

What is the current understanding of FGF19 genetic variations and their functional significance?

Research on FGF19 genetic variations has revealed:

• FGF19 gene variants:

  • Two common SNPs (rs948992 and rs1789170) in the FGF19 gene were investigated but not found to be associated with bile acid diarrhea

  • Unlike FGF21, where loss-of-function variants have been extensively characterized, FGF19 loss-of-function in humans is less well documented, likely because it would increase bile acids to toxic levels

• FGF19 copy number variations:

  • Increased FGF19 copy number is frequently detected in hepatocellular carcinoma

  • This suggests that FGF19 amplification may contribute to carcinogenesis

• Co-receptor (KLB) variations:

  • SNP rs17618244 in KLB has been associated with colonic transit in patients with diarrhea-predominant irritable bowel, presumably due to altered bile acid metabolism from decreased FGF19 activity

  • A KLB locus was associated with increased alcohol consumption in a meta-analysis of over 105,000 individuals

  • SNP rs2608819 in KLB has been associated with reduced KLB expression in adipose tissue and higher BMI

  • rs17618244 SNP is associated with increased risk of ballooning and lobular inflammation in children with NAFLD These genetic insights help explain individual variability in FGF19 function and disease susceptibility, particularly in liver and metabolic disorders.