Fibroblast Growth Factor 19 Expression Research Articles

Role of serum endotoxin, FGF19, TLR2, TNF-α, IL-12 and IL-10 in NAFLD-associated T2DM pathogenesis: Insights into Th1 bias and protective mechanisms.

Non-alcoholic fatty liver disease (NAFLD) in non-obese patients is pathophysiologically distinct, exhibiting common immunological link with type-2 diabetes mellitus (T2DM). This study aims to delineate the role of Toll-like receptor 2 (TLR2)-mediated immuno-modulation along with its association with fibroblast growth factor receptor 4 (FGFR4) and its ligand fibroblast growth factor 19 (FGF19) in the pathogenesis of NAFLD without or with T2DM. Blood samples were collected from patients with NAFLD (n = 90), NAFLD with T2DM (n = 90) and healthy cohorts (n = 90) with consent and clinical records. Real-time polymerase chain reaction (PCR), enzyme-linked immunoassay (ELIZA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to analyze messenger ribonucleic acid (mRNA), protein expression and gene polymorphism. The molecular genetic analysis revealed the prevalence of variant allele(A) in FGFR4 gene in both cases compared to controls. The mRNA expression of FGF19 and TLR2 exhibited significant upregulation in NAFLD without T2DM compared to NAFLD with T2DM. Tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) showed upregulation in both disease cohorts compared to control while IL-10 showed significant downregulation in NAFLD with T2DM compared to the other two cohorts. Correlation analysis between FGF19 and TLR2 revealed significant positive association in both NAFLD with and without T2DM. The Th1:Th2 ratio showed significant upregulation in NAFLD with T2DM compared to NAFLD without T2DM. In conclusion, elevated serum endotoxin levels appear to contribute to NAFLD and T2DM development. Upregulated FGF19 seems to be protective against developing T2DM in NAFLD patients. Higher TLR2, TNF-α and IL-12 expression in NAFLD without T2DM suggests a Th1 bias in its pathogenesis, while reduced IL-10 in NAFLD with T2DM implies a more skewed Th1 state in this condition.

Enteral Agonism of the Farnesoid X Receptor-Fibroblast Growth Factor 19 Axis Prevents Cholestasis in TPN-Fed Piglets

Total parenteral nutrition (TPN) administration provides necessary nutrients to infants who cannot tolerate enteral feedings. However, the use of TPN can result in cholestasis which can cause parenteral nutrition-associated liver diseases. Previous mitigation strategies for cholestasis have included administering bile acids enterally to encourage normal bile acid metabolism. The objective of this study was to determine if treatment of either ursodeoxycholic acid (UDCA), Tropifexor (TPX), or fibroblast growth factor 19 (FGF19) will prevent cholestasis in a piglet TPN model through the activation of the farnesoid X receptor (FXR)-FGF19 axis. We hypothesize that UDCA will have minimum effects on FXR while TPX, a potent FXR agonist, will significantly affect the FXR pathway, and FGF19 will reduce bile acid synthesis to alleviate cholestasis. Piglets received TPN for 3 weeks and were treated enterally with either UDCA (25 mg/kg*day) or TPX (7.5 μg/kg*day) with minimal milk-based formula (12 mL/kg*day), or daily intravenous FGF19 (0.25 mg/d) injection. Body weight gain was not different after 3 weeks. Plasma markers of cholestasis such as of total bile acids, bilirubin, and gamma-glutamyl transferase were lower in pigs that received TPX compared to the control treatment at the end of the study. Circulating levels of FGF19 and tissue concentrations of total bile acids were not different across treatments. In the ileum, TPX increased mRNA expression of FGF19, ileal lipid binding protein, and organic solute transporter α compared to the control pigs. All treatments reduced the mRNA expression of apical sodium-dependent bile acid transporter compared to the control treatment. TPX also increased mRNA expression of small heterodimer protein and bile salt export pump in the liver. Overall, we conclude that UDCA and FGF19 had minimal effects on cholestasis, whereas TPX prevented cholestasis in part via activation of the FXR-FGF19 axis in TPN fed piglets. NIDDK R01-DK094616 K01 DK129408 T32 NIH grant DK07664. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

FXR-FGF19 signaling in the gut–liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence

Background and aimsExperimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut–liver axis and their link to disease severity in patients with cirrhosis.MethodsPatients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured.ResultsSystemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = −0.512, p < 0.001) and BA (r = −0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls.ConclusionsFXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut–liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis.Clinical trial number: NCT03267615Graphical abstractPhysiology of enterohepatic FXR-FGF19 signaling and its regulation in patients with advanced chronic liver disease (ACLD). (FXR) farnesoid X receptor; (FGF19) fibroblast growth factor 19; (BA) bile acids; (c/dACLD) compensated/decompensated advanced chronic liver disease; (FXR) farnesoid X receptor; (SHP) small heterodimer partner; (OST-α/-β) organic solute transporter subunit alpha/beta; (CYP7A1) cholesterol 7 alpha-hydroxylase; (NTCP) Na+-taurocholate cotransporting polypeptide; (CYP8B1) sterol 12-alpha-hydroxylase; (HVPG) hepatic venous pressure gradient; (TJ) tight junctions; (AMP) antimicrobial peptides; (ASBT) Apical Sodium Dependent Bile Acid Transporter; (ZO 1) zonula occludens-1; (OCLN) occluding; (DEFA5) alpha-5-defensin.

Fibroblast Growth Factor 19 Alters Bile Acids to Induce Dysbiosis in Mice With Alcohol-Induced Liver Disease

Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic+ binge ethanol feeding. After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge. Chronic+ binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfβ, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens. Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.

Decreased FXR Agonism in the Bile Acid Pool Is Associated with Impaired FXR Signaling in a Pig Model of Pediatric NAFLD.

The objective of this study was to investigate whether the impairment of farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in juvenile pigs with non-alcoholic fatty liver disease (NAFLD) is associated with changes in the composition of the enterohepatic bile acid pool. Eighteen 15-day-old Iberian pigs, pair-housed in pens, were allocated to receive either a control (CON) or high-fructose, high-fat (HFF) diet. Animals were euthanized in week 10, and liver, blood, and distal ileum (DI) samples were collected. HFF-fed pigs developed NAFLD and had decreased FGF19 expression in the DI and lower FGF19 levels in the blood. Compared with the CON, the HFF diet increased the total cholic acid (CA) and the CA to chenodeoxycholic acid (CDCA) ratio in the liver, DI, and blood. CA and CDCA levels in the DI were negatively and positively correlated with ileal FGF19 expression, respectively, and blood levels of FGF19 decreased with an increasing ileal CA to CDCA ratio. Compared with the CON, the HFF diet increased the gene expression of hepatic 12-alpha-hydrolase, which catalyzes the synthesis of CA in the liver. Since CA species are weaker FXR ligands than CDCA, our results suggest that impairment of FXR-FGF19 signaling in NAFLD pigs is associated with a decrease in FXR agonism in the bile acid pool.

FGF19 promotes nasopharyngeal carcinoma progression by inducing angiogenesis via inhibiting TRIM21-mediated ANXA2 ubiquitination

PurposeNasopharyngeal carcinoma (NPC) has characteristics of high invasion and early metastasis. Most NPC patients present with locoregionally advanced illness when first diagnosed. Therefore, it is urgent to discover NPC biomarkers. Fibroblast growth Factor 19 (FGF19) plays a role in various physiological or pathological processes, including cancer. In this research, we discovered the importance of FGF19 in NPC, and clarified its role in tumour angiogenesis.MethodsWestern blotting, immunohistochemistry and ELISA were used to investigate FGF19 expression in NPC. Then we took CCK8, colony formation, Transwell and wound healing assays to identify the influence of FGF19 on NPC malignant behaviours. The proliferative and metastatic capacity of FGF19 were evaluated in nude mice and zebrafish. The role of FGF19 in angiogenesis was investigated by tube formation and Matrigel plug angiogenesis assays. We then evaluated the variation in Annexin A2(ANXA2) levels with the treatment of FGF19. Lastly, co-immunoprecipitation and ubiquitination assays were performed to identify the mechanisms involved.ResultsFGF19 levels were elevated in tissues and serum of NPC patients and were associated with poor clinical stages. High expression of FGF19 promoted NPC malignant behaviours. In particular, FGF19 expression was correlated with microvessel density in tissues and NPC-derived FGF19 could accelerate angiogenesis in vitro and in vivo. Mechanistically, FGF19 influenced ANXA2 expression to promote angiogenesis. Moreover, tripartite motif-containing 21(TRIM21) interacted with ANXA2 and was responsible for ANXA2 ubiquitination.ConclusionFGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.

Analysis of the Bile Acid Composition in a Fibroblast Growth Factor 19-Expressing Liver-Humanized Mouse Model and Its Use for CYP3A4-Mediated Drug-Drug Interaction Studies.

Numerous biomedical applications have been described for liver-humanized mouse models, such as in drug metabolism or drug-drug interaction (DDI) studies. However, the strong enlargement of the bile acid (BA) pool due to lack of recognition of murine intestine-derived fibroblast growth factor-15 by human hepatocytes and a resulting upregulation in the rate-controlling enzyme for BA synthesis, cytochrome P450 (CYP) 7A1, may pose a challenge in interpreting the results obtained from such mice. To address this challenge, the human fibroblast growth factor-19 (FGF19) gene was inserted into the Fah-/- , Rag2-/- , Il2rg-/- NOD (FRGN) mouse model, allowing repopulation with human hepatocytes capable of responding to FGF19. While a decrease in CYP7A1 expression in human hepatocytes from humanized FRGN19 mice (huFRGN19) and a concomitant reduction in BA production was previously shown, a detailed analysis of the BA pool in these animals has not been elucidated. Furthermore, there are sparse data on the use of this model to assess potential clinical DDI. In the present work, the change in BA composition in huFRGN19 compared with huFRGN control animals was systematically evaluated, and the ability of the model to recapitulate a clinically described CYP3A4-mediated DDI was assessed. In addition to a massive reduction in the total amount of BA, FGF19 expression in huFRGN19 mice resulted in significant changes in the profile of various primary, secondary, and sulfated BAs in serum and feces. Moreover, as observed clinically, administration of the pregnane X receptor agonist rifampicin reduced the oral exposure of the CYP3A4 substrate triazolam. SIGNIFICANCE STATEMENT: Transgenic expression of FGF19 normalizes the unphysiologically high level of bile acids in a chimeric liver-humanized mouse model and leads to massive changes in bile acid composition. These adaptations could overcome one of the potential impediments in the use of these mouse models for drug-drug interaction studies.

FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer.

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion aremarkedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, thisstudy describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Exploring the role of FXR signaling in maintaining ileal mucosa integrity in subjects with altered glucose tolerance conditions

Aim: Treatment with the FXR agonist obeticholic acid (OCA) has been found to improve glucose metabolism in type 2 diabetes (T2DM) subjects with mechanisms not completely elucidated. In the gut, FXR is mainly expressed in the ileum where promotes transcription of fibroblast growth factor-19 (FGF19) having positive effects on glucose homeostasis, and maintains gut barrier integrity by regulating tight-junction (TJ) proteins expression. Herein, we evaluate whether subjects with dysglycemic conditions exhibit a down-regulation of the intestinal FXR-FGF19-TJ axis and whether treatment with OCA may revert this aberration. Methods: Levels of FXR, FGF19 and TJ proteins and pro-inflammatory cytokines were assessed in ileal mucosa specimens collected during colonoscopy from 53 subjects subdivided according to their glucose tolerance in: NGT (n=26), prediabetes (n=12) and T2DM (n=15). Effects of OCA treatment was assessed on ileal mucosa specimens of subjects with prediabetes or T2DM cultured in absence or presence of OCA for 6h. Results: Ileal FXR protein and mRNA levels were progressively decreased in prediabetes (-26%) and T2DM (-34%) as compared to the NGT group (both P&lt;0.05). Ileal FXR downregulation was paralleled by lower FGF19 expression and circulating levels (both P&lt;0.05). Additionally, we observed a progressive decrease of proteins and mRNA levels of the TJ zonulin (ZO)-1, occludin and claudin-1 (P&lt;0.05 for all) with an activation of pro-inflammatory pathways in the ileal mucosa of subjects with prediabetes and T2DM as compared to the NGT group. OCA treatment resulted in an up-regulation of FGF19 expression and release (both P&lt;0.01), mRNA and protein levels of the TJ ZO-1, occludin and claudin-1 and in reduced pro-inflammatory cytokines synthesis and release (P&lt;0.05 for all). Conclusion: FXR stimulation by OCA treatment reverts the altered FGF-19/TJ axis in subjects with prediabetes and T2DM, indicating intestinal FXR signaling as a novel target for prevention and/or treatment of T2DM.

FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer.

Chemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown. Next-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms. In this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells. FGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.

Fibroblast growth factor 19 secretion and function in perinatal development.

Limited work has focused on fibroblast growth factor-19 (FGF19) secretion and function in the perinatal period. FGF19 is a potent growth factor that coordinates development of the brain, eye, inner ear, and skeletal system in the embryo, but after birth, FGF19 transitions to be an endocrine regulator of the classic pathway of hepatic bile acid synthesis. FGF19 has emerged as a mediator of metabolism and bile acid synthesis in aged animals and adults in the context of liver disease and metabolic dysfunction. FGF19 has also been shown to have systemic insulin-sensitizing and skeletal muscle hypertrophic effects when induced or supplemented at supraphysiological levels in adult rodent models. These effects could be beneficial to improve growth and nutritional outcomes in preterm infants, which are metabolically resistant to the anabolic effects of enteral nutrition. Existing clinical data on FGF19 secretion and function in the perinatal period in term and preterm infants has been equivocal. Studies in pigs show that FGF19 expression and secretion are upregulated with gestational age and point to molecular and endocrine factors that may be involved. Work focused on FGF19 in pediatric diseases suggests that augmentation of FGF19 secretion by activation of gut FXR signaling is associated with benefits in diseases such as short bowel syndrome, parenteral nutrition-associated liver disease, and biliary atresia. Future work should focus on characterization of FGF19 secretion and the mechanism underpinning the transition of FGF19 function as an embryological growth factor to metabolic and bile acid regulator.

Increased Circulating Cortisol After Vaginal Birth Is Associated With Increased FGF19 Secretion in Neonatal Pigs.

The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean vs vaginal birth on the development of bile acid and fibroblast growth factor 19 (FGF19) signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent cesarean delivery on gestation day 105 (n = 2) and 114 (n = 2; term = 115 days), and 2 additional sows were allowed to farrow at term (gestation days 112 and 118). Piglets were euthanized at birth (Term-Vaginal n = 6; Term-Cesarean n = 8; Preterm n = 10) for tissue and blood collection, and the remaining pigs received total parenteral nutrition then were fed enterally on day 3 (Term-Vaginal n = 8; Term-Cesarean n = 10; Preterm n = 8), before blood and tissue were collected. Piglets born vaginally had a markedly (30-fold) higher plasma FGF19 at birth than term pigs born via cesarean delivery, and 70-fold higher than preterm pigs (P < 0.001). However, distal ileum FGF19 gene expression was similar in all groups (P > 0.05). Plasma FGF19 positively correlated with plasma cortisol (r = 0.58; P < 0.05) and dexamethasone treatment increased ileal FGF19 expression in cultured pig tissue explants and human enteroids. Our findings suggest that exposure to maternal or endogenous glucocorticoids in the perinatal period may upregulate the development of the bile acid-FGF19 pathway.

Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition-fed piglets.

Long-term parenteral nutrition (PN) causes PN-associated liver disease, for which therapeutic approaches are limited. This study aimed to investigate the effects of Lactobacillus plantarum CGMCC 1258 (LP) on liver and intestinal injury in PN-fed neonatal piglets. The piglets received PN with or without oral LP for 14 days. The levels of liver enzymes and inflammatory markers were measured using biochemical kits and quantitative real-time polymerase chain reaction. Serum fibroblast growth factor 19 (FGF19) was detected using an enzyme-linked immunosorbent assay. The bile acid (BA) profiles in the liver, serum, and intestinal contents were determined using ultraperformance liquid chromatography coupled with mass spectrometry. The composition of intestinal bacteria was analyzed with 16S rRNA gene amplicon sequencing. LP supplementation was associated with improved markers of liver disease, inflammation, and oxidative stress in PN-fed piglets. Moreover, markers of intestinal injury and inflammation were alleviated by LP in PN-fed piglets. Mechanistically, LP increased the abundance of Lactobacillus in ileal contents and stimulated FGF19 expression in ileal mucosa. Subsequently, it increased the expression of small heterodimer partner (SHP) and inhibited cholesterol 7α-hydroxylase (CYP7A1) expression in the liver. Additionally, LP altered the systemic composition and metabolism of BAs. LP alleviated liver and intestinal injury in PN-fed neonatal piglets by altering the composition of intestinal bacteria and BAs.

Abstract 2689: FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue

Abstract Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Barriers to screening reduces compliance and negatively impacts patient outcomes, necessitating alternatives. A blood-based approach provides a more convenient and accessible modality, but serum markers are lacking. Using a meta-transcriptomics approach, we identified Fibroblast Growth Factor 19 (FGF19), an enteroendocrine FGF responsible for bile acid (BA) homeostasis, as an attractive CRC marker. However, whether FGF19 is aberrantly secreted into blood by colorectal tumors or induces endocrine-like paraneoplastic effects is unknown. To assess the strength of FGF19 as a CRC biomarker, expression data from the Genotype-Tissue Expression consortium (GTEx), The Cancer Genome Atlas (TCGA-COADREAD), and our curated Meta-dataset (E-MTAB-10089) were downloaded and analyzed for associations with prognostic indicators. Next, in silico FGF19 expression profiles were validated in vitro using a panel of five CRC cell lines via western blot with secretion quantitated by sandwich ELISA. To determine whether colorectal tumors contribute FGF19 to circulation, subcutaneous xenografts of HCT116 and Colo201 cells were established in four male and female NOD Scid gamma (NSG) mice. Tumor volume, as well as serum and urine FGF19 were assessed weekly over a 36-day period. Following euthanasia, murine liver and ileal tissue were processed for downstream mRNA and bile acid quantification. To determine if malignant FGF19 exerts paraneoplastic effects RNA sequencing was performed on hepatic mRNA using the Illumina NovaSeq 6000 system. Reads were processed, aligned, mapped, and analyzed for differential expression and functional enrichment using an integrated informatics pipeline implemented in R. Meta-transcriptomics revealed that ectopic overexpression of FGF19 was highly indicative of CRC and associated with unfavorable prognostic indicators including disease progression, treatment failure, and poor survival. In vitro testing recapitulated in silico findings, showing that that four out of five CRC cell lines constitutively express and secrete FGF19. We also readily detected FGF19 in serum and urine of mice harboring xenografts derived from Colo201, but not HCT116, cells. Moreover, circulating FGF19 levels increased with tumor size and exerted paraneoplastic effects on liver tissue such as suppression of BA synthesis, dysregulation of cholesterol metabolism, and induction of pre-neoplasia. In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing. Citation Format: Michael Walter Rohr, Jordan Beardsley, Sai Preethi Nakkina, Dexter Hadley, Deborah Altomare. FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2689.

Maternal and Fetal Bile Acid Homeostasis Regulated by Sulfated Progesterone Metabolites through FXR Signaling Pathway in a Pregnant Sow Model.

Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by Student’s t-test or one-way ANOVA of GraphPad Prism and further compared by using the Student–Newman–Keuls test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of FGF19 in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.

Effects of BBR on growth performance, serum and hepatic biochemistry parameters, hepatic morphology and gene expression levels related to glucose metabolism in largemouth bass, Micropterus salmoides

An 8-week experiment was performed to investigate the effects of BBR on growth performance, hepatic glucose metabolism, antioxidant capacity, liver histology and intestinal digestive enzyme activity of largemouth bass. Fish (initial weight ≈122 g) were randomly allocated into 16 cages (280 L, 30 fish per tank) and fed four isonitrogenous and isolipidic diets containing 0, 0.5, 1 and 2 g/kg BBR respectively. The results indicated that diets with 1 and 2 g/kg BBR significantly promoted growth, decreased serum glucose, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol but increased serum high-density lipoprotein cholesterol (p < 0.05). The application of BBR significantly decreased hepatic alanine aminotransferase, TG and TC but increased hepatic superoxide dismutase and catalase (p < 0.05). Diets with 1 and 2 g/kg BBR significantly decreased hepatic malondialdehyde, aspartate aminotransferase and hepatic glycogen but increased intestinal farnesoid X receptor and fibroblast growth factor-19 expression and dramatically altered its downstream glycolysis- and gluconeogenesis-related genes, along with their enzyme activities (p < 0.05). Supplementation with BBR increased (p < 0.05) intestinal protease activity in B5, B10 and B20, lipase activity in B10 and B20 and amylase activity in B20. BBR reduced the liver voiding rate and fat content. These results indicated that dietary supplementation with BBR at 1 and 2 g/kg was beneficial for promoting growth and health in largemouth bass. The improved glycolysis and inhibited gluconeogenesis may account for the reduced hyperglycaemia by BBR. In addition, enhancing the activity of intestinal digestive enzymes is an effective way for BBR to improve carbohydrate utilization in largemouth bass.

Downregulation of Serum and Distal Ileum Fibroblast Growth Factor19 in Bile Acid Diarrhoea Patients.

Bile acid diarrhoea or BAD is a common but little recognised cause of chronic diarrhoea. Few of these patients in China have been diagnosed due to a lack of diagnostic options. To clarify the diagnostic value of serum fibroblast growth factor19 (FGF19) in BAD patients. We reported on 60 chronic diarrhoea patients and 80 healthy volunteers (HV). Based on the 90th percentile levels of serum 7a-hydroxy-4-cholesten-3-one (C4) of HV, these patients were divided into BAD group (C4 ≥ 90th) and non-bile acid diarrhoea group (NBAD, C4 < 90th). Serum FGF19 in the two clinical groups and HV group were compared, as was distal ileum FGF19 in clinical groups. The diagnostic value of serum FGF19 for BAD was evaluated. The 90th percentile of serum C4 in HV group was 65.87ng/ml. Serum FGF19 concentrations in BAD group (Median 69.28pg/ml; n = 23) were significantly lower than those in HV (Median 122.18pg/ml; n = 80) and NBAD (Median 129.57pg/ml; n = 29) groups. FGF19 mRNA of the distal ileum in BAD group, was lower than that in NBAD group, P = 0.002. The rate of FGF19 protein low expression of distal ileum in BAD and NBAD group were 78.3% and 48.3%, P = 0.027. Using an ROC curve, statistical analysis yielded a threshold FGF19 concentration of 117.3pg/ml (AUC, 0.906; 91.3% sensitivity, 79.3% specificity) for a clinical diagnosis of BAD. Serum and distal ileum expression of FGF19 significantly decreased in BAD patients. The suggested clinical ranges for serum FGF19 < 117.3pg/ml has high sensitivity and specificity for BAD patients with a normal structural and histological ileum.

FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.

Rapid Postnatal Upregulation of Intestinal Farnesoid X Receptor-Fibroblast Growth Factor 19 Signaling in Premature Pigs.

Bile acid (BA) homeostasis is regulated by intestinal cellular signaling involving the farnesoid X receptor (FXR) and fibroblast growth factor 19 (FGF19) secretion. Using preterm and term pigs as a model, we examined postnatal changes in expression of the FXR-FGF19 axis that is poorly characterized in human infants. Pigs delivered by caesarean section at 10-day preterm and near full term (115-day gestation) were fitted with orogastric and umbilical arterial catheters. Pigs were fed combined parenteral nutrition and minimal enteral nutrition for 5 days, followed by milk formula until 26 d days. Plasma and tissue samples were collected at days 0, 5, 11, and 26. Plasma FGF19 concentration and liver and distal intestinal gene expression of FGF19 and other FXR target genes were quantified. Plasma FGF19 levels were lower in preterm versus term newborn pigs (P < 0.05), increased markedly by 5 days, especially in preterm pigs, and decreased in both groups until day 26. Likewise, intestinal FXR and FGF19 expression was lower (P ≤ 0.05) in premature versus term newborn pigs and decreased (P ≤ 0.05) between days 5 and 26. Hepatic expression of cholesterol 7α-hydroxylase (CYP7A1) was inversely correlated with plasma FGF19 in both groups. We conclude that the activity of FXR-FGF19 axis is lower in preterm than in term newborn pigs but increases transiently and then declines by the first month of age. We also provide supportive evidence of negative feedback between plasma FGF19 and hepatic CYP7A1 expression.

Changes of serum FGF19 and PEDF levels in patients with type 2 diabetic retinopathy

Objective To observe the expression of FGF19 ( fibroblast growth factor 19) and PEDF (pigment epithelium-derived factor) in the serum of type 2 diabetic retinopathy (DR) patients and discuss their significance. Methods Total 89 patients with type 2 diabetes were selected and divided into two groups according to whether they were combined with diabetic retinopathy: 45 patients with type 2 diabetes alone (DM group) and 44 patients with type 2 diabetes mellitus combined with retinopathy (DR group). At the same time, 40 healthy people were selected as the control group (NDM group). The serum levels of FGF19 and PEDF and their biochemical indexes were detected and compared in each group. The correlation between the indexes and the relationship between FGF19, PEDF and DR were analyzed. Results Compared with NDM group, serum FGF19 level in DM group and DR group decreased, while C-reactive protein (CRP) and PEDF level in DM group and DR group increased (P 0.05); the levels of Hcy, triacylglycerol (TG) and CRP in DR group were higher than those in DM and NDM group (P 12.76 mg/L, the sensitivity and specificity of PEDF dignosing DR were 80.9% and 56.7% respectively. Conclusions In patients with DR, serum FGF19 level decreased and serum PEDF levels increased. The level of both changes is closely related to DR and may be involved in the development of DR. Key words: Diabetic retinopathy; Diabetes mellitus, type 2; Fibroblast growth factor 19; Pigment epithelium derived factor