Endocrine fibroblast growth factors as regulators of metabolic homeostasis

Endocrine fibroblast growth factors (FGFs) function as hormones that maintain specific metabolic states by controlling homeostasis of bile acid, glucose, fatty acid, phosphate, and vitamin D. Endocrine FGFs exert their biological activity through a common design of coreceptor system consisting of the Klotho gene family of transmembrane proteins and cognate FGF receptors. Moreover, expression of endocrine FGFs is regulated by nuclear receptors whose lipophilic ligands are generated under the control of these hormones in the target organs. Thus, novel endocrine axes have emerged that regulate diverse metabolic processes through feedback loops composed of the FGF, Klotho, FGF receptor, and nuclear receptor gene families. This review summarizes the role of Klotho family proteins in the regulation of metabolic activity and expression of the endocrine FGFs. © 2009 International Union of Biochemistry and Molecular Biology, Inc.

[1]  T. Miloh,et al.  beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[2]  M. Kuro-o.  Endocrine FGFs and Klothos: emerging concepts , 2008, Trends in Endocrinology & Metabolism.

[3]  K. Rosenblatt,et al.  Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1 , 2008, Proceedings of the National Academy of Sciences.

[4]  S. Kliewer,et al.  Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. , 2008, Cell metabolism.

[5]  P. Arner,et al.  FGF21 attenuates lipolysis in human adipocytes – A possible link to improved insulin sensitivity , 2008, FEBS letters.

[6]  J. D. Dunbar,et al.  FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho , 2008, Journal of cellular physiology.

[7]  Masashi Suzuki,et al.  betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. , 2008, Molecular endocrinology.

[8]  C. Brownstein,et al.  A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism , 2008, Proceedings of the National Academy of Sciences.

[9]  S. Fukumoto.  Actions and mode of actions of FGF19 subfamily members. , 2008, Endocrine journal.

[10]  N. Itoh,et al.  Functional evolutionary history of the mouse Fgf gene family , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  S. Leeman,et al.  Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17 , 2007, Proceedings of the National Academy of Sciences.

[12]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[13]  L. Qiang,et al.  Identification of a Domain within Peroxisome Proliferator-Activated Receptor γ Regulating Expression of a Group of Genes Containing Fibroblast Growth Factor 21 That Are Selectively Repressed by SIRT1 in Adipocytes , 2007, Molecular and Cellular Biology.

[14]  B. Lemon,et al.  Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling* , 2007, Journal of Biological Chemistry.

[15]  C. Blackmore,et al.  Liver-specific Activities of FGF19 Require Klotho beta* , 2007, Journal of Biological Chemistry.

[16]  S. Kliewer,et al.  Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21* , 2007, Journal of Biological Chemistry.

[17]  K. White,et al.  A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. , 2007, Journal of musculoskeletal & neuronal interactions.

[18]  C. Kahn,et al.  Endocrine regulation of ageing , 2007, Nature Reviews Molecular Cell Biology.

[19]  T. Lundåsen,et al.  PPARα is a key regulator of hepatic FGF21 , 2007 .

[20]  M. Razzaque,et al.  Mineral metabolism and aging: the fibroblast growth factor 23 enigma , 2007, Current opinion in nephrology and hypertension.

[21]  Aditi Gupta,et al.  Emerging role of fibroblast growth factor 23 in a bone–kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization , 2007, Current opinion in nephrology and hypertension.

[22]  Shinzo Tanaka,et al.  α-Klotho as a Regulator of Calcium Homeostasis , 2007, Science.

[23]  David D Moore.  Sister Act , 2007, Science.

[24]  J. Flier,et al.  Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. , 2007, Cell metabolism.

[25]  S. Kliewer,et al.  Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. , 2007, Cell metabolism.

[26]  K. Rosenblatt,et al.  βKlotho is required for metabolic activity of fibroblast growth factor 21 , 2007, Proceedings of the National Academy of Sciences.

[27]  S. Kliewer,et al.  Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members , 2007, Molecular and Cellular Biology.

[28]  F. Mehrbod,et al.  Molecular determinants of FGF‐21 activity—synergy and cross‐talk with PPARγ signaling , 2007, Journal of cellular physiology.

[29]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[30]  M. Razzaque,et al.  Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. , 2006, The American journal of pathology.

[31]  S. Kliewer,et al.  Identification of a hormonal basis for gallbladder filling , 2006, Nature Medicine.

[32]  L. Bonewald,et al.  Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism , 2006, Nature Genetics.

[33]  T. Strom,et al.  DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis , 2006, Nature Genetics.

[34]  Daniel L. Koller,et al.  The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. , 2006, The Journal of clinical endocrinology and metabolism.

[35]  J. Gromada,et al.  Fibroblast Growth Factor-21 Improves Pancreatic β-Cell Function and Survival by Activation of Extracellular Signal–Regulated Kinase 1/2 and Akt Signaling Pathways , 2006, Diabetes.

[36]  T. Strom,et al.  Polypeptide GalNAc-transferase T3 and Familial Tumoral Calcinosis , 2006, Journal of Biological Chemistry.

[37]  Xi Jiang,et al.  Pathogenic role of Fgf23 in Hyp mice. , 2006, American journal of physiology. Endocrinology and metabolism.

[38]  M. Razzaque,et al.  Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. , 2006, Trends in molecular medicine.

[39]  Shaun K Olsen,et al.  Receptor Specificity of the Fibroblast Growth Factor Family , 2006, Journal of Biological Chemistry.

[40]  M. Razzaque,et al.  Premature aging‐like phenotype in fibroblast growth factor 23 null mice is a vitamin D‐mediated process , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[42]  Philippe Lefebvre,et al.  Sorting out the roles of PPARα in energy metabolism and vascular homeostasis , 2006 .

[43]  K. White,et al.  Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. , 2005, Endocrinology.

[44]  J. Hoenderop,et al.  The ß-Glucuronidase Klotho Hydrolyzes and Activates the TRPV5 Channel , 2005, Science.

[45]  S. Kliewer,et al.  Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. , 2005, Cell metabolism.

[46]  Animesh Nandi,et al.  Suppression of Aging in Mice by the Hormone Klotho , 2005, Science.

[47]  R. Quigley,et al.  Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. , 2005, Kidney international.

[48]  Y. Nabeshima,et al.  Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. , 2005, The Journal of clinical investigation.

[49]  J. Gromada,et al.  FGF-21 as a novel metabolic regulator. , 2005, The Journal of clinical investigation.

[50]  Shaun K Olsen,et al.  Structural basis for fibroblast growth factor receptor activation. , 2005, Cytokine & growth factor reviews.

[51]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[52]  D. Arking,et al.  Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity , 2005, Circulation research.

[53]  R. Soriano,et al.  Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. , 2004, Endocrinology.

[54]  Y. Mishina,et al.  Deletion of Dentin Matrix Protein-1 Leads to a Partial Failure of Maturation of Predentin into Dentin, Hypomineralization, and Expanded Cavities of Pulp and Root Canal during Postnatal Tooth Development* , 2004, Journal of Biological Chemistry.

[55]  B. Henrissat,et al.  Klotho Is a Novel β-Glucuronidase Capable of Hydrolyzing Steroid β-Glucuronides* , 2004, Journal of Biological Chemistry.

[56]  J. Chiang.  Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. , 2004, Journal of hepatology.

[57]  Y. Takeuchi,et al.  Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. , 2004, The Journal of clinical investigation.

[58]  T. Blundell,et al.  The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. , 2004, Biochemistry.

[59]  Y. Takeuchi,et al.  FGF‐23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[60]  K. Fukuda,et al.  Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. , 2003, Molecular endocrinology.

[61]  D. Russell.  The enzymes, regulation, and genetics of bile acid synthesis. , 2003, Annual review of biochemistry.

[62]  D. Arking,et al.  KLOTHO allele status and the risk of early-onset occult coronary artery disease. , 2003, American journal of human genetics.

[63]  D. Miao,et al.  The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency* , 2003, The Journal of Biological Chemistry.

[64]  T. Spector,et al.  Klotho Gene Polymorphisms Associated With Bone Density of Aged Postmenopausal Women , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[65]  M. Kuro-o,et al.  Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. , 2002, Bone.

[66]  I. Mian,et al.  Association of human aging with a functional variant of klotho , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Y. Nabeshima,et al.  Molecular cloning and expression analyses of mouse βklotho, which encodes a novel Klotho family protein , 2000, Mechanisms of Development.

[69]  T. Meitinger,et al.  Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 , 2000, Nature Genetics.

[70]  N. Itoh,et al.  Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. , 2000, Biochemical and biophysical research communications.

[71]  Sander Kersten,et al.  Roles of PPARs in health and disease , 2000, Nature.

[72]  C. Deng,et al.  Elevated Cholesterol Metabolism and Bile Acid Synthesis in Mice Lacking Membrane Tyrosine Kinase Receptor FGFR4* , 2000, The Journal of Biological Chemistry.

[73]  A. Goddard,et al.  FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. , 1999, Cytokine.

[74]  W. Wahli,et al.  Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting , 1999 .

[75]  Tadashi Kaname,et al.  Mutation of the mouse klotho gene leads to a syndrome resembling ageing , 1997, Nature.

[76]  C. Goodyer,et al.  Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. , 1997, The Journal of clinical investigation.

[77]  A. Poustka,et al.  A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets , 1995, Nature Genetics.

[78]  Yoshiji Yamada,et al.  Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women , 2004, Journal of Molecular Medicine.

[79]  D. French,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity , 2022 .