Targeting FXR and FGF19 to Treat Metabolic Diseases—Lessons
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
FGF19 Protects Hepatocellular Carcinoma Cells Against Endoplasmic Reticulum Stress Via Activation of FGFR4-Gsk3β-Nrf2 Signaling
Author Manuscript Published OnlineFirst on September 26, 2017; DOI: 10.1158/0008-5472.CAN-17-2039 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3β-Nrf2 signaling Yong Teng1,2#*, Huakan Zhao3,4#, Lixia Gao1, Wenfa Zhang3, Austin Y Shull5, Chloe Shay6 1. Department of Oral Biology, Augusta University, Augusta, GA, USA 2. Georgia Cancer Center, Augusta University, Augusta, GA, USA 3. School of Life Sciences, Chongqing University, Chongqing, China 4. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China 5. Department of Biology, Presbyterian College, Clinton, SC, USA 6. Emory Children’s Center, Emory University, Atlanta, GA, USA # These authors contributed equally to this work Running Title: Role of FGF19 in ER stress Key Words: FGF19, FGFR4, Nrf2, HCC, ER stress, anticancer Abbreviations list: AARE: amino-acid-response element; ANOVA: analysis of variance; ARE: antioxidant response elements; ATF4: activating transcription factor 4; ChIP-qPCR: chromatin immunoprecipitation quantitative-PCR; CV: cyclic voltammetry; DMSO: dimethyl sulfoxide; EMT: epithelial-mesenchymal transition; ER: endoplasmic reticulum; FGF19: fibroblast growth factor 19; FGFR4: FGF receptor 4; GSK3β: glycogen synthase kinase •− 3β; HCC: hepatocellular carcinoma; Nrf2: nuclear factor E2-related factor 2; O2 : superoxide; PBS: phosphate-buffered saline; ROS: reactive free -
ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are The
0031-3998/07/6103-0267 PEDIATRIC RESEARCH Vol. 61, No. 3, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are the Predominant FGF Ligands Expressed in Human Fetal Growth Plate Cartilage PAVEL KREJCI, DEBORAH KRAKOW, PERTCHOUI B. MEKIKIAN, AND WILLIAM R. WILCOX Medical Genetics Institute [P.K., D.K., P.B.M., W.R.W.], Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Obstetrics and Gynecology [D.K.] and Department of Pediatrics [W.R.W.], UCLA School of Medicine, Los Angeles, California 90095 ABSTRACT: Fibroblast growth factors (FGF) regulate bone growth, (G380R) or TD (K650E) mutations (4–6). When expressed at but their expression in human cartilage is unclear. Here, we deter- physiologic levels, FGFR3-G380R required, like its wild-type mined the expression of entire FGF family in human fetal growth counterpart, ligand for activation (7). Similarly, in vitro cul- plate cartilage. Using reverse transcriptase PCR, the transcripts for tivated human TD chondrocytes as well as chondrocytes FGF1, 2, 5, 8–14, 16–19, and 21 were found. However, only FGF1, isolated from Fgfr3-K644M mice had an identical time course 2, 17, and 19 were detectable at the protein level. By immunohisto- of Fgfr3 activation compared with wild-type chondrocytes and chemistry, FGF17 and 19 were uniformly expressed within the showed no receptor activation in the absence of ligand (8,9). growth plate. In contrast, FGF1 was found only in proliferating and hypertrophic chondrocytes whereas FGF2 localized predominantly to Despite the importance of the FGF ligand for activation of the resting and proliferating cartilage. -
Up-Regulation of Fibroblast Growth Factor 19 and Its Receptor Associates with Progression from Fatty Liver to Hepatocellular Carcinoma
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 32 Research Paper Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma Yan Li1,*, Weizhong Zhang2,*, Anne Doughtie1, Guozhen Cui3, Xuanyi Li1, Harshul Pandit1, Yingbin Yang1, Suping Li1, Robert Martin1 1Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, 40202, USA 2Department of Hand Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, 130022, China 3Department of Hepatology, Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China *These authors contributed equally to this work Correspondence to: Yan Li, email: [email protected] Robert Martin, email: [email protected] Keywords: hepatocellular carcinoma, FGF19, FGFR4, cancer stem cell Received: February 08, 2016 Accepted: June 12, 2016 Published: July 21, 2016 ABSTRACT Background: Human fibroblast growth factor 19 (FGF19), its receptor (FGFR4) and EpCAM play an important role in cell proliferation, differentiation, motility, and overexpression have been linked to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the FGF19 signals responsible for the progression of HCC arising from fatty liver. Results: FGF19 level was significantly increased in the HCC patients’ serum compared to non-HCC controls. The IHC results demonstrated significant increases of protein expressions of FGF19, FGFR4 and EpCAM in specimens with fatty liver, NASH, cirrhosis, and HCC compared to healthy liver tissue. There was a significant positive correlation between the protein expressions (FGF19, FGFR4, and EpCAM) and histopathologic changes from FL to HCC. Furthermore, FGF19 was positively correlated with FGFR4 and with EpCAM. -
FGF21 Acts As a Negative Regulator of Bile Acid Synthesis
237 2 Journal of M M Chen, C Hale et al. FGF21 negative regulator of bile 237:2 139–152 Endocrinology acid metabolism RESEARCH FGF21 acts as a negative regulator of bile acid synthesis Michelle M Chen*, Clarence Hale*, Shanaka Stanislaus, Jing Xu and Murielle M Véniant Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California, USA Correspondence should be addressed to M M Véniant: [email protected] *(M M Chen and C Hale contributed equally to this work) Abstract Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid Key Words homeostasis in vivo; its most closely related subfamily member, FGF19, is known to be a f FGF21 critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a f Fc-fusion protein functional role in bile acid metabolism, we evaluated the effects of short- and long-term f β-klotho binding exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, f bile acid gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited Cyp7A1 mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50–60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cholesterol and fatty acid excretions were elevated. -
FGF Signaling Network in the Gastrointestinal Tract (Review)
163-168 1/6/06 16:12 Page 163 INTERNATIONAL JOURNAL OF ONCOLOGY 29: 163-168, 2006 163 FGF signaling network in the gastrointestinal tract (Review) MASUKO KATOH1 and MASARU KATOH2 1M&M Medical BioInformatics, Hongo 113-0033; 2Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo 104-0045, Japan Received March 29, 2006; Accepted May 2, 2006 Abstract. Fibroblast growth factor (FGF) signals are trans- Contents duced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS- 1. Introduction RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/ 2. FGF family GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS~ 3. Regulation of FGF signaling by WNT MAPK signaling cascade is implicated in cell growth and 4. FGF signaling network in the stomach differentiation, the PI3K~AKT signaling cascade in cell 5. FGF signaling network in the colon survival and cell fate determination, and the PI3K~aPKC 6. Clinical application of FGF signaling cascade in cell polarity control. FGF18, FGF20 and 7. Clinical application of FGF signaling inhibitors SPRY4 are potent targets of the canonical WNT signaling 8. Perspectives pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. 1. Introduction Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, Fibroblast growth factor (FGF) family proteins play key roles while recombinant FGF2 protein and FGF4 expression vector in growth and survival of stem cells during embryogenesis, are applicable for therapeutic angiogenesis. Helicobacter tissues regeneration, and carcinogenesis (1-4). -
Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB
Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB Chaofeng Yang1, Chengliu Jin1, Xiaokun Li3, Fen Wang1, Wallace L. McKeehan1,2, Yongde Luo1,2* 1 Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America, 2 IBT Proteomics and Nanotechnology Laboratory, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America, 3 School of Pharmacy, Wenzhou Medical College, Wenzhou, China Abstract Background: Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear. Methodology/Principal Findings: We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. -
A Bioinformatics Model of Human Diseases on the Basis Of
SUPPLEMENTARY MATERIALS A Bioinformatics Model of Human Diseases on the basis of Differentially Expressed Genes (of Domestic versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes Vasiliev1,2 G, Chadaeva2 I, Rasskazov2 D, Ponomarenko2 P, Sharypova2 E, Drachkova2 I, Bogomolov2 A, Savinkova2 L, Ponomarenko2,* M, Kolchanov2 N, Osadchuk2 A, Oshchepkov2 D, Osadchuk2 L 1 Novosibirsk State University, Novosibirsk 630090, Russia; 2 Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia; * Correspondence: [email protected]. Tel.: +7 (383) 363-4963 ext. 1311 (M.P.) Supplementary data on effects of the human gene underexpression or overexpression under this study on the reproductive potential Table S1. Effects of underexpression or overexpression of the human genes under this study on the reproductive potential according to our estimates [1-5]. ↓ ↑ Human Deficit ( ) Excess ( ) # Gene NSNP Effect on reproductive potential [Reference] ♂♀ NSNP Effect on reproductive potential [Reference] ♂♀ 1 increased risks of preeclampsia as one of the most challenging 1 ACKR1 ← increased risk of atherosclerosis and other coronary artery disease [9] ← [3] problems of modern obstetrics [8] 1 within a model of human diseases using Adcyap1-knockout mice, 3 in a model of human health using transgenic mice overexpressing 2 ADCYAP1 ← → [4] decreased fertility [10] [4] Adcyap1 within only pancreatic β-cells, ameliorated diabetes [11] 2 within a model of human diseases -
Markers of Liver Regeneration—The Role of Growth Factors and Cytokines
Hoffmann et al. BMC Surgery (2020) 20:31 https://doi.org/10.1186/s12893-019-0664-8 RESEARCH ARTICLE Open Access Markers of liver regeneration—the role of growth factors and cytokines: a systematic review Katrin Hoffmann*†, Alexander Johannes Nagel†, Kazukata Tanabe, Juri Fuchs, Karolin Dehlke, Omid Ghamarnejad, Anastasia Lemekhova and Arianeb Mehrabi Abstract Background: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. Methods: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. Results: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. Conclusion: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address -
Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis
Diabetes Volume 70, July 2021 1443 Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis Alexandre Picard, Salima Metref, David Tarussio, Wanda Dolci, Xavier Berney, Sophie Croizier, Gwena€el Labouebe, and Bernard Thorens Diabetes 2021;70:1443–1457 | https://doi.org/10.2337/db20-1121 The counterregulatory response to hypoglycemia is an between the brain and these peripheral tissues is ensured, essential survival function. It is controlled by an inte- in large part, by the autonomic nervous system. This is grated network of glucose-responsive neurons, which activated in response to changes in the concentration of trigger endogenous glucose production to restore nor- circulating hormones such as insulin, leptin, or ghrelin moglycemia. The complexity of this glucoregulatory and of nutrients such as glucose and lipids. Glucose-re- network is, however, only partly characterized. In a ge- sponsive neurons, which increase their firing activity in netic screen of a panel of recombinant inbred mice we response to hyperglycemia (glucose-excited [GE] neurons) METABOLISM fi previously identi ed Fgf15, expressed in neurons of the or to hypoglycemia (glucose-inhibited [GI] neurons) (1–3), dorsomedial hypothalamus (DMH), as a negative regula- are thought to couple fluctuations in blood glucose con- tor of glucagon secretion. Here, we report on the gener- centrations to the regulation of sympathetic or parasym- ation of Fgf15CretdTomato mice and their use to further pathetic nerve activity. characterize these neurons. We show that they were A major glucoregulatory role of the central nervous sys- glutamatergic and comprised glucose-inhibited and tem is to maintain glycemic levels at a minimum value of glucose-excited neurons. -
Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System
REVIEW published: 07 November 2017 doi: 10.3389/fnins.2017.00617 Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System Kim L. Mertens 1, Andries Kalsbeek 2, 3, 4, Maarten R. Soeters 2 and Hannah M. Eggink 2, 4* 1 Master’s Program in Biomedical Sciences, University of Amsterdam, Amsterdam, Netherlands, 2 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 3 Laboratory of Endocrinology, Department Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, 4 Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, Netherlands Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not Edited by: restricted to the gastrointestinal tract, but can affect different tissues throughout the Miguel López, Universidade de Santiago de organism. It is still unclear whether these effects also involve signaling of bile acids to Compostela, Spain the central nervous system (CNS). Bile acid signaling to the CNS encompasses both Reviewed by: direct and indirect pathways. Bile acids can act directly in the brain via central FXR and Angel Nadal, TGR5 signaling. In addition, there are two indirect pathways that involve intermediate Universidad Miguel Hernández de Elche, Spain agents released upon interaction with bile acids receptors in the gut. Activation of Joseph Pisegna, intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 University of California, Los Angeles, United States (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. -
FGF19/SOCE/Nfatc2 Signaling Circuit Facilitates the Self
1 FGF19/SOCE/NFATc2 signaling circuit facilitates the self- 2 renewal of liver cancer stem cells 3 4 Jingchun Wang 1†, Huakan Zhao2†*, Lu Zheng3†, Yu Zhou2, Lei Wu2, Yanquan Xu1, Xiao 5 Zhang1, Guifang Yan2, Halei Sheng1, Rong Xin1, Lu Jiang1, Juan Lei2, Jiangang Zhang1, Yu 6 Chen2, Jin Peng1, Qian Chen1, Shuai Yang1, Kun Yu1, Dingshan Li1, Qichao Xie4*, 7 Yongsheng Li1,2* 8 9 1Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, 10 Chongqing 400037, China. 11 2Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 12 400030, China. 13 3Department of Hepatobiliary Surgery, Xinqiao Hospital, Army Medical University, 14 Chongqing 400037, China. 15 4Department of Oncology, The Third Affiliated Hospital, Chongqing Medical University, 16 Chongqing 401120, China 17 18 †These authors contributed equal to this work. 19 *Correspondence ([email protected]) (H.Z.), ([email protected]) (Q.X.), 20 ([email protected]) (Y.L.). 21 22 Running title: FGF19-NFATc2 signaling promotes self-renewal of LCSCs. 23 Keywords: FGF19; Self-renewal; SOCE; NFATc2, LCSCs 24 1 25 Abstract 26 Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and 27 correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast 28 growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor 29 prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is 30 unknown. 31 Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were 32 characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and 33 tumorigenic potential assays. -
51338269.Pdf
UNIVERSITÉ DE SHERBROOKE Dérégulation de l’axe endocrine FGF15/FGF4 lors d’infection du système entérohépatique. Par Guillaume Romain, B. Sc. Département de Microbiologie et Infectiologie Laboratoire d’Alfredo Menendez Mémoire présenté à la Faculté de médecine et des sciences de la santé en vue de l’obtention du grade de Maître ès sciences (M.Sc) en microbiologie Sherbrooke, Québec, Canada Juillet 2014 Membre du jury Pr. Alfredo Menendez (Ph. D.), Département de Microbiologie et Infectiologie Pr. Louis-Charles Fortier (Ph. D.), Département de Microbiologie et Infectiologie Pre. Julie Carrier (M. D.), Département de médecine, service de gastro-entérologie ii Résumé Dérégulation de l’axe endocrine FGF15/FGF4 lors d’infection du système entérohépatique. Par Guillaume Romain Département de microbiologie et infectiologie Mémoire présentée à la Faculté de médecine et des sciences de la santé Faculté de médecine et sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4 Fibroblast Growth Factor 19 (FGF19 chez l’humain ; FGF15 chez la souris) est un régulateur central du métabolisme hépatique. Cette molécule a un impact important au niveau de la différentiation neurologique et de l’oreille interne au stade fœtal. À l’âge adulte, le patron d’expression est restreint au système gastro-intestinal. Contrairement aux autres membres de la superfamille des FGFs, FGF19/15 agit de manière endocrine car il n’est pas retenu par la matrice extracellulaire et peut rejoindre la circulation sanguine. L’expression de FGF19/15 est induite par les acides biliaires au niveau de l’intestin grêle, plus précisément l’iléon. Les acides biliaires lient le récepteur nucléaire Farnesoid-X- Receptor (FXR) qui peut ensuite s’hétérodimériser avec Retinoid-X-Receptor (RXR) pour se lier au promoteur de FGF19/15, ce qui enclenche son expression.