Exploring endocrine FGFs - structures, functions and biomedical applications.

The family of fibroblast growth factors (FGFs) consists of 22 members with diverse biological functions in cells, from cellular development to metabolism. The family can be further categorized into three subgroups based on their three modes of action. FGF19, FGF21, and FGF23 are endocrine FGFs that act in a hormone-like/endocrine manner to regulate various metabolic activities. However, all three members of the endocrine family require both FGF receptors (FGFRs) and klotho co-receptors to elicit their functions. α-klotho and ß-klotho act as scaffolds to bring endocrine FGFs closer to their receptors (FGFRs) to form active complexes. Numerous novel studies about metabolic FGFs' structures, mechanisms, and physiological insights have been published to further understand the complex molecular interactions and physiological activities of endocrine FGFs. Herein, we aim to review the structures, physiological functions, binding mechanisms to cognate receptors, and novel biomedical applications of endocrine FGFs in recent years.

Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs.

BACKGROUND & AIMS: We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. METHODS: Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. RESULTS: Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. CONCLUSIONS: Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatohepatitis (MASH), represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol).  After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BA) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the downregulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.

Clinical value of fibroblast growth factor 19 in predicting gastrointestinal dysfunction in patients with sepsis.

Objective: To assess the potential value of fibroblast growth factor 19 (FGF19) as a predictor of gastrointestinal (GI) dysfunction in patients with sepsis. Methods: A prospective study was conducted, and 209 patients who were diagnosed with sepsis and admitted to the intensive care unit (ICU) at teaching hospitals in China were enrolled from June 2023 to December 2023. The serum FGF19 level was determined at ICU admission. The differences in serum FGF19 levels between the two groups were compared via the Mann-Whitney U test, and Spearman's correlation coefficient was used to identify the correlations of the FGF19 concentration with other clinical variables and biomarkers. Receiver operating characteristic (ROC) analysis was used to determine the value of FGF19 in predicting GI dysfunction in patients with sepsis. Results: The total ICU mortality rate was 13.3% (24/180). There was a tendency toward increased ICU mortality in patients with sepsis-associated GI dysfunction compared with patients without GI dysfunction with statistical significance (21.9% vs. 8.6%, p = 0.031). Serum FGF19 levels were significantly higher in patients with sepsis-associated GI dysfunction than in patients without GI dysfunction [355.1 (37.2, 2315.4) µg/mL vs. 127.4 (5.7, 944.2) µg/mL, p = 0.003]. The results of receiver operating characteristic (ROC) curve analysis revealed that the area under the ROC curve (AUC) for the ability of FGF19 to predict GI dysfunction in patients with sepsis was 0.773 (95% CI 0.712 ~ 0.827), which was greater than the predictive capacity of PCT [AUC = 0.632 (95% CI 0.562 ~ 0.804)]. Conclusion: Serum FGF19 could be considered as a novel predictor or biomarker of GI dysfunction in patients with sepsis.

Gut-muscle communication links FGF19 levels to the loss of lean muscle mass following rapid weight loss.

OBJECTIVE: Optimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity. RESEARCH DESIGN AND METHODS: Weight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED. RESULTS: Postprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass. CONCLUSION: These data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss.

Post-Bariatric Hypoglycemia: an Impaired Metabolic Response to a Meal.

AIMS/HYPOTHESIS: Post-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH. METHODS: We performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH. RESULTS: Out of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH. CONCLUSION: Overall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH.

Dissecting the mediating role of inflammatory factors in the interaction between metabolites and sepsis: insights from bidirectional Mendelian randomization.

Sepsis, a life-threatening condition, involves complex interactions among metabolic alterations, inflammatory mediators, and host responses. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationships between 1400 metabolites and sepsis, and the mediating role of inflammatory factors. We identified 36 metabolites significantly associated with sepsis (p < 0.05), with AXIN1, FGF-19, FGF-23, IL-4, and OSM showing an inverse association, suggesting a protective role, while IL-2 exhibited a positive correlation, indicating a potential risk factor. Among these metabolites, Piperine and 9-Hydroxystearate demonstrated particularly interesting protective effects against sepsis. Piperine's protective effect was mediated through its interaction with AXIN1, contributing to a 16.296% reduction in sepsis risk. This suggests a potential pathway where Piperine influences sepsis outcomes by modulating AXIN1 levels. 9-Hydroxystearate also exhibited a protective role against sepsis, mediated through its positive association with FGF-19 and negative association with IL-2, contributing 9.436% and 12.565%, respectively, to its protective effect. Experimental validation confirmed significantly elevated IL-2 levels and reduced FGF-19, AXIN1, piperine, and 9-hydroxyoctadecanoic acid levels in sepsis patients compared to healthy controls. Piperine levels positively correlated with AXIN1, while 9-hydroxyoctadecanoic acid levels negatively correlated with IL-2 and positively correlated with FGF-19, supporting the Mendelian randomization findings. Our findings provide insights into the molecular mechanisms of sepsis, highlighting the unique roles and contributions of specific metabolites and their interactions with inflammatory mediators. This study enhances our understanding of sepsis pathophysiology and opens avenues for targeted therapeutic interventions and biomarker development for sepsis management. However, further research is essential to validate these pathways across diverse populations and fully explore the roles of these metabolites in sepsis.

PTX promotes breast cancer migration and invasion by recruiting ATF4 to upregulate FGF19.

BACKGROUND: Widely-spread among women, breast cancer is a malignancy with fatalities, and chemotherapy is a vital treatment option for it. Recent studies have underscored the potential of chemotherapeutic agents such as paclitaxel, adriamycin, cyclophosphamide, and gemcitabine, among others, in facilitating tumor metastasis, with paclitaxel being extensively researched in this context. The molecular mechanism of these genes and their potential relevance to breast cancer is noteworthy. METHOD: Clinical tissue specimens were used to analyze the expression and clinical significance of FGF19 or P-FGFR4 in patients with breast cancer before and after chemotherapy. qRT-PCR, ELISA, immunofluorescence and Western blotting were used to detect the expression level of FGF19 in breast cancer cells. The biological impacts of paclitaxel, FGF19, and ATF4 on breast cancer cells were assessed through CCK8, Transwell, and Western blot assays. The expression of ATF4 in breast cancer cells was determined through database analysis, Western blot analysis, qRT-PCR, and immunofluorescence. The direct interaction between FGF19 and ATF4 was confirmed by a luciferase assay, and Western blotting was used to assess the levels of key proteins in the stress response pathway. To confirm the effects of PTX and FGF19 in vivo, we established a lung metastasis model in nude mice. RESULTS: FGF19 expression was increased in breast cancer patients after chemotherapy. Paclitaxel can boost the migration and invasion of breast cancer cells, accompanied by an increase in FGF19 expression. ATF4 might be involved in facilitating the enhancing effect of FGF19 on breast cancer cell migration. Finally, stimulation during paclitaxel treatment could trigger a stress response, influencing the expression of FGF19 and the migration of breast cancer cells. CONCLUSION: These data suggest that paclitaxel regulates FGF19 expression through ATF4 and thus promotes breast cancer cell migration and invasion.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

OBJECTIVE AND DESIGN: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. METHODS: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. RESULTS: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. CONCLUSION: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

The role of FGF19 in metabolic regulation: insights from preclinical models to clinical trials.

Fibroblast growth factor 19 (FGF19) is a hormone synthesized in enterocytes in response to bile acids. This review explores the pivotal role of FGF19 in metabolism, addressing the urgent global health concern of obesity and its associated pathologies, notably type 2 diabetes. The intriguing inverse correlation between FGF19 and body mass or visceral adiposity, as well as its rapid increase following bariatric surgery, emphasizes its potential as a therapeutic target. This article meticulously examines the impact of FGF19 on metabolism by gathering evidence primarily derived from studies conducted in animal models or cell lines, using both FGF19 treatment and genetic modifications. Overall, these studies demonstrate that FGF19 has antidiabetic and antiobesogenic effects. A thorough examination across metabolic tissues, including the liver, adipose tissue, skeletal muscle, and the central nervous system, is conducted, unraveling the intricate interplay of FGF19 across diverse organs. Moreover, we provide a comprehensive overview of clinical trials involving an FGF19 analog called aldafermin, emphasizing promising results in diseases such as nonalcoholic steatohepatitis and diabetes. Therefore, we aim to foster a deeper understanding of FGF19 role and encourage further exploration of its clinical applications, thereby advancing the field and offering innovative approaches to address the escalating global health challenge of obesity and related metabolic conditions.

Endocrine fibroblast growth factors in domestic animals.

Fibroblast growth factors (FGFs) are a group of structurally homologous yet functionally pleiotropic proteins. Canonical and intracellular FGFs have primarily autocrine or paracrine effects. However, the FGF19 subfamily, composed of FGF15/19, FGF21, and FGF23, act as endocrine hormones that regulate bile acid, metabolic, and phosphorus homeostasis, respectively. Current research in human and rodent models demonstrates the potential of these endocrine FGFs to target various diseases, including disorders of inherited hypophosphatemia, chronic liver disease, obesity, and insulin resistance. Many diseases targeted for therapeutic use in humans have pathophysiological overlaps in domestic animals. Despite the potential clinical and economic impact, little is known about endocrine FGFs and their signaling pathways in major domestic animal species compared with humans and laboratory animals. This review aims to describe the physiology of these endocrine FGFs, discuss their current therapeutic use, and summarize the contemporary literature regarding endocrine FGFs in domestic animals, focusing on potential future directions.

Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL.

PURPOSE: At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. METHODS: In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. RESULTS: Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. CONCLUSION: Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study.

BACKGROUND AND AIMS: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. METHODS: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. RESULTS: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. CONCLUSIONS: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.

Efficacy and safety of aldafermin in non-alcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is an advanced subtype of non-alcoholic fatty liver disease (NAFLD). NASH prevalence is increasing exponentially and carries a high risk for disease progression, cirrhosis, and liver-related mortality. Aldafermin, a fibroblast growth factor 19 (FGF19) analog, is one of the evolving therapeutic agents with the potential to regulate multiple pathways involved in the pathogenesis of NASH. We aimed to investigate the efficacy and safety of aldafermin in patients with NASH. METHODS: PubMed, Scopus, Cochrane Library, and Web of Science were searched till November 2023 to identify eligible randomized controlled trials (RCTs). Continuous data were pooled as mean difference (MD), while dichotomous data were pooled as risk ratios (RR) with a 95 % confidence interval. A subgroup meta-analysis was conducted to evaluate the efficacy of the two doses (1 mg and 3 mg) of aldafermin. RESULTS: Four RCTs with a total of 491 patients were included. Aldafermin showed a dose-dependent improvement in the ≥30 % reduction in the liver fat content (RR: 2.16, 95 % CI [1.41 to 3.32]) and (RR: 5.00, 95 % CI [1.34 to 18.64]), alanine aminotransferase levels (MD: -19.79, 95 % CI [-30.28 to -9.3]) and (MD: -21.91, 95 % CI [-29.62 to -14.21]), aspartate aminotransferase levels (MD: -11.79, 95 % CI [-18.06 to -5.51]) and (MD: -13.9, 95 % CI [-18.59 to -9.21]), and enhanced liver fibrosis score (ELF) (MD: -0.13, 95 % CI [-0.29 to 0.02]) and (MD: -0.33, 95 % CI [-0.50 to -0.17]), in the 1 mg and 3 mg subgroups respectively. No significant differences were detected in the aldafermin group regarding histologic endpoints, lipid profile, metabolic parameters, and overall adverse effects, except for the increased occurrence of diarrhea in the aldafermin 3 mg subgroup. CONCLUSION: Aldafermin is a promising well-tolerated therapeutic agent for NASH with evidence supporting its ability to reduce liver fat content, fibrosis serum biomarkers, and liver enzymes. However, its effectiveness in improving histologic fibrosis, while showing numerical trends, still lacks statistical significance. Larger and longer NASH trials are warranted to enhance the robustness of the evidence.

Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling.

OBJECTIVE: Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility. METHODS: In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline. RESULTS: Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043). CONCLUSION: Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.

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

BACKGROUND AND AIMS: Experimental 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. METHODS: Patients 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. RESULTS: Systemic 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. CONCLUSIONS: FXR-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: NCT03267615.

The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression.

BACKGROUND: The FGF/FGFR signaling pathway plays a critical role in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway, in epithelial ovarian cancer (EOC) and strategies on overcoming AZD4547 resistance. METHODS: The effect of AZD4547 on cell viability/migration was evaluated and in vivo experiments in intraperitoneal xenografts using EOC cells and a patient-derived xenograft (PDX) model were performed. The effect of the combination of AZD4547 with SU11274, a c-Met-specific inhibitor, FGF19-specific siRNA, or an FGFR4 inhibitor was evaluated by MTT assay. RESULTS: AZD4547 significantly decreased cell survival and migration in drug-sensitive EOC cells but not drug-resistant cells. AZD4547 significantly decreased tumor weight in xenograft models of drug-sensitive A2780 and SKOV3ip1 cells and in a PDX with drug sensitivity but not in models with drug-resistant A2780-CP20 and SKOV3-TR cells. Furthermore, c-Met expression was high in SKOV3-TR and HeyA8-MDR cells, and co-administration of SU11274 and AZD4547 synergistically induced cell death. In addition, expressions of FGF19 and FGFR4 were high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20 cells. CONCLUSIONS: This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis.

FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone's metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone's oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.

Predictive value of serum fibroblast growth factor 19 and liver stiffness for intestinal failure associated liver disease-cholestasis.

BACKGROUND: Intestinal failure associated liver disease (IFALD)-cholestasis is a common complication of long-term parenteral nutrition (PN) in patients with intestinal failure (IF). The lack of effective early identification indicators often results in poor clinical outcomes. The objective of this study was to evaluate the predictive value of serum FGF19 and liver stiffness in IFALD-cholestasis. METHODS: Eligible adults diagnosed with IF were identified from Jinling Hospital in China. Diagnostic criteria for IFALD-cholestasis: total bilirubin >1 mg/dL and conjugated bilirubin >0.3 mg/dL for ≥6 months. Fasting blood specimens were prospectively collected and serum FGF19 concentrations were determined using ELISA and liver stiffness was measured by Two-dimensional shear wave elastography. Binary logistic regression analysis identified predictors of IFALD-cholestasis. Receiver operating characteristic (ROC) curves and areas under the ROC curves (AUROC) were used to evaluate the accuracy of serum FGF19 and liver stiffness in identifying IFALD-cholestasis. RESULTS: Of 203 study patients with IF, 70 (34.5%) were diagnosed with IFALD-cholestasis. The serum FGF19 levels in those with IFALD-cholestasis were significantly decreased compared with those in patients without, and liver stiffness was significantly increased (p < 0.001). Multivariate logistic regression analyses suggested that intestinal discontinuity, dependence on PN, liver stiffness >6.5 kPa, and serum FGF19 ≤107 pg/mL were independent risk factors for IFALD-cholestasis. The AUROC for serum FGF19 and liver stiffness, which indicate the occurrence of IFALD-cholestasis, were 0.810 and 0.714, respectively. Serum FGF19 had a superior predictive performance than liver stiffness (p < 0.05). CONCLUSION: Both low circulating serum FGF19 concentration and increased liver stiffness are excellent predictors of IFALD-cholestasis, but serum FGF19 is superior to increased liver stiffness in predicting IFALD-cholestasis.

Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases.

Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.