FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

Wu, Ai-Luen; Coulter, Sally; Liddle, Christopher; Wong, Anne; Eastham-Anderson, Jeffrey; French, Dorothy; Peterson, Andrew S.; Sonoda, Junichiro

doi:10.1371/journal.pone.0017868

Cited by 150 publications

(179 citation statements)

References 37 publications

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“…7B ). In hepatocytes and liver cancer cells, FGF19 has been shown to signal through FGFR4 ( 31 ). In line with these fi ndings, we found that the 3 cell lines expressed signifi cantly high levels of FGFR4 mRNA ( Fig.…”

supporting

confidence: 83%

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

et al. 2012

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Patient stratifi cation biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identifi cation of patient stratifi cation biomarkers for NVP-BGJ398, a novel and selective fi broblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the fi rst time, we report oncogenic FGFR1 amplifi cation in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our fi ndings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identifi ed predictors of sensitivity. SIGNIFICANCE:The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefi t the most from any given drug. To this end, we have integrated the molecular profi les for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specifi c patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118-33.

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confidence: 83%

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

et al. 2012

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“…Strong FGFR4 mRNA was detected in hepatocytes adjacent to central vein by in situ hybridization, and the hepatic dysplasia foci and BrdU labeling from FGF19 transgenic livers are also located around central vein. In addition, activation of FGFR4 alone was sufficient to induce hepatocyte proliferation (Wu et al, 2010a;Wu et al, 2010b) and FGF19 induced hepatocytes proliferation was not observed in FGFR4 knockout mice, confirming the role played by FGFR4 in hepatocarcinogenesis (Wu et al, 2011).…”

Section: Fgf Pathwaymentioning

confidence: 79%

Signaling Pathways in Liver Cancer

Wu¹,

Li²

2012

Liver Tumors

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“…This occurs in the liver via activation of hepatic FGFR4, hence completing a negative feedback loop on bile acid synthesis ( 16 ). In addition, FGF19 has been shown to affect expression of other Cyp enzymes that may lead to alterations in bile acid pool composition ( 17 ). However, given that the elimination of cholesterol is primarily through conversion to bile acids and subsequently excreted, FGF19 treatment would be expected not only to reduce bile acid levels but also to increase cholesterol levels.…”

Section: Serum Triglyceride Cholesterol and Bile Acids Measurementmentioning

confidence: 99%

“…FGF19 activates FGFR4, which is predominantly expressed in the liver, and activation of this receptor by FGF19 has been shown to reduce the bile acid pool size ( 16,25 ) and affect bile acid composition ( 17 ). This pathway has been proposed as the enterohepatic signal that mediates postprandial inhibition of bile acid synthesis ( 16,25 ).…”

Section: Acute Fgf19 Treatment Also Increased Plasma Tg Levels In Diementioning

confidence: 99%

Dual actions of fibroblast growth factor 19 on lipid metabolism

Baribault

et al. 2013

Journal of Lipid Research

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hormone ( 3 ). In lieu of heparan sulfate binding, FGF19 requires a protein cofactor, ␤ Klotho, to effectively interact with and activate FGF receptors ( 4-6 ). The requirement for a co-receptor is a unique feature common to the FGF19 subfamily and is further exemplifi ed by another subfamily member, FGF21, which also lacks heparan sulfate affi nity and uses ␤ Klotho as its co-receptor ( 4 ). Consistent with their shared ability to use the same co-receptor for signaling, there is extensive overlap in the reported pharmacological effects of FGF19 and FGF21. FGF19 and FGF21 transgenic mice, as well as chronic administration of recombinant FGF19 or FGF21 proteins, similarly lowered serum glucose, triglyceride (TG), and cholesterol levels and improved insulin sensitivity and reduced body weight in high-fat diet-induced obesity models ( 7-9 ). Chronic treatment with FGF19 or FGF21 similarly reduced blood glucose levels and improved glucose disposal in ob/ob (B6.V-Lep ob /J) leptin-defi cient mice; however, plasma TG and cholesterol levels after treatment with FGF19 have not been reported in this model ( 8,9 ).The common co-receptor for FGF19 and FGF21, ␤ Klotho, is a single-pass transmembrane protein with two homologous extracellular domains that share sequence homology to ␤ -glucosidases in bacteria and plants ( 10 ). ␤ Klotho has a short intracellular domain and is unlikely to signal by itself. Its primary role is believed to mediate interactions between these two FGF molecules and FGF receptors (FGFR) to activate FGFR tyrosine kinase activity ( 11 ). ␤ Klotho interacts with only four of the seven major FGFRs, the "c" isoforms of FGFR1, -2, -3. and -4 ( 11 ). FGF19 and FGF21 can activate FGFR1c, -2c, and -3c complexed with ␤ Klotho in vitro ( 4, 6, 11-13 ). Recent results using an engineered FGF19 variant with altered receptor specifi city Abstract Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fi broblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specifi cities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.VLep ob /J leptin-defi cient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed signifi cant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising an...

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FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

Cited by 150 publications

References 37 publications

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Signaling Pathways in Liver Cancer

Dual actions of fibroblast growth factor 19 on lipid metabolism

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