Klotho and βKlotho

  • Makoto Kuro-o
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 728)

Abstract

Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. FGF21 is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. FGF23 is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases.

Keywords

Saccharide Hypogonadism Rickets Calcinosis Hyperphosphatemia 

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References

  1. 1.
    Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390(6655):45–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Kuroo M, Hanaoka K, Hiroi Y et al. Salt-sensitive hypertension in transgenic mice overexpressing Na(+)-proton exchanger. Circ Res 1995; 76(1):148–153.Google Scholar
  3. 3.
    Matsumura Y, Aizawa H, Shiraki-Iida T et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 1998; 242(3):626–630.PubMedCrossRefGoogle Scholar
  4. 4.
    Shiraki-Iida T, Aizawa H, Matsumura Y et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998; 424(1–2):6–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Mian IS. Sequence, structural, functional and phylogenetic analyses of three glycosidase families. Blood Cells Mol Dis 1998; 24(2):83–100.PubMedCrossRefGoogle Scholar
  6. 6.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117(12):4003–4008.PubMedGoogle Scholar
  7. 7.
    Kamemori M, Ohyama Y, Kurabayashi M et al. Expression of Klotho protein in the inner ear. Hear Res 2002; 171(1-2):103–110.PubMedCrossRefGoogle Scholar
  8. 8.
    Wolf I, LevanonCohen S, Bose S et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 2008; 27(56):7094–7105.PubMedCrossRefGoogle Scholar
  9. 9.
    Tsujikawa H, Kurotaki Y, Fujimori T et al. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003; 17(12):2393–2403.PubMedCrossRefGoogle Scholar
  10. 10.
    Kashimada K, Yamashita T, Tsuji K et al. Defects in growth and bone metabolism in klotho mutant mice are resistant to GH treatment. J Endocrinol 2002; 174(3):403–410.PubMedCrossRefGoogle Scholar
  11. 11.
    Toyama R, Fujimori T, Nabeshima Y et al. Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho-deficient mice. Endocrinology 2006; 147(1):120–129.PubMedCrossRefGoogle Scholar
  12. 12.
    Min D, Panoskaltsis-Mortari A, Kuro-o M et al. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007; 109(6):2529–2537.PubMedCrossRefGoogle Scholar
  13. 13.
    Nakatani T, Sarraj B, Ohnishi M et al. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) — mediated regulation of systemic phosphate homeostasis. FASEB J 2009; 23(2):433–441.PubMedCrossRefGoogle Scholar
  14. 14.
    Liu H, Fergusson MM, Castilho RM et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317(5839):803–806.PubMedCrossRefGoogle Scholar
  15. 15.
    Manabe N, Kawaguchi H, Chikuda H et al. Connection between B lymphocyte and osteoclast differentiation pathways. J Immunol 2001; 167(5):2625–2631.PubMedGoogle Scholar
  16. 16.
    Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol 2004; 5(2):133–139.PubMedCrossRefGoogle Scholar
  17. 17.
    Kawaguchi H, Manabe N, Miyaura C et al. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 1999; 104(3):229–237.PubMedCrossRefGoogle Scholar
  18. 18.
    Yamashita T, Nifuji A, Furuya K et al. Elongation of the epiphyseal trabecular bone in transgenic mice carrying a klotho gene locus mutation that leads to a syndrome resembling aging. J Endocrinol 1998; 159(1):1–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Yamashita T, Yamashita M, Noda M et al. High-resolution micro-computed tomography analyses of the abnormal trabecular bone structures in klotho gene mutant mice. J Endocrinol 2000; 164(2):239–245.PubMedCrossRefGoogle Scholar
  20. 20.
    Fukuchi Y. The aging lung and chronic obstructive pulmonary disease: similarity and difference. Proc Am Thorac Soc 2009; 6(7):570–572.PubMedCrossRefGoogle Scholar
  21. 21.
    Suga T, Kurabayashi M, Sando Y et al. Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. Am J Respir Cell Mol Biol 2000; 22(1):26–33.PubMedGoogle Scholar
  22. 22.
    Ishii M, Yamaguchi Y, Yamamoto H et al. Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. J Gerontol A Biol Sci Med Sci 2008; 63(12):1289–1298.PubMedCrossRefGoogle Scholar
  23. 23.
    Sato A, Hirai T, Imura A et al. Morphological mechanism of the development of pulmonary emphysema in klotho mice. Proc Natl Acad Sci USA 2007; 104(7):2361–2365.PubMedCrossRefGoogle Scholar
  24. 24.
    Nagai T, Yamada K, Kim HC et al. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 2003; 17(1):50–52.PubMedGoogle Scholar
  25. 25.
    Anamizu Y, Kawaguchi H, Seichi A et al. Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol (Berl) 2005; 109(5):457–466.CrossRefGoogle Scholar
  26. 26.
    Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113):787–795.PubMedCrossRefGoogle Scholar
  27. 27.
    Yamamoto M, Clark JD, Pastor JV et al. Regulation of oxidative stress by the anti-aging hormone Klotho. J Biol Chem 2005; 280(45):38029–38034.PubMedCrossRefGoogle Scholar
  28. 28.
    Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10):6120–6123.CrossRefGoogle Scholar
  29. 29.
    White KE, Evans WE, O’Rlordan JLH et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3):345–348.CrossRefGoogle Scholar
  30. 30.
    White KE, Carn G, Lorenz-Depiereux B et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 2001; 60(6):2079–2086.PubMedCrossRefGoogle Scholar
  31. 31.
    Shimada T, Kakitani M, Yamazaki Y et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113(4):561–568.PubMedGoogle Scholar
  32. 32.
    Razzaque MS, Sitara D, Taguchi T et al. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006; 20(6):720–722.PubMedGoogle Scholar
  33. 33.
    Yu X, Ibrahimi OA, Goetz R et al. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 2005; 146(11):4647–4656.PubMedCrossRefGoogle Scholar
  34. 34.
    Goetz R, Beenken A, Ibrahimi OA et al. Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of FGF19 Subfamily Members. Mol Cell Biol 2007; 27:3417–3428.PubMedCrossRefGoogle Scholar
  35. 35.
    Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444(7120):770–774.PubMedCrossRefGoogle Scholar
  36. 36.
    Tomiyama K, Maeda R, Urakawa I et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc Natl Acad Sci USA 2010; 107(4):1666–1671.PubMedCrossRefGoogle Scholar
  37. 37.
    Farrow EG, Davis SI, Summers LJ et al. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 2009; 20(5):955–960.PubMedCrossRefGoogle Scholar
  38. 38.
    Ichikawa S, Imel EA, Kreiter ML et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117:2692–2701.CrossRefGoogle Scholar
  39. 39.
    Brown EM, Gamba G, Riccardi D et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366(6455):575–580.PubMedCrossRefGoogle Scholar
  40. 40.
    Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19(3):429–435.PubMedCrossRefGoogle Scholar
  41. 41.
    Saji F, Shiizaki K, Shimada S et al. Regulation of fibroblast growth factor 23 production in bone in uremic rats. Nephron Physiol 2009; 111(4):59–66.CrossRefGoogle Scholar
  42. 42.
    Ohnishi M, Nakatani T, Lanske B, Razzaque MS. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 2009; 75:1166–1172.PubMedCrossRefGoogle Scholar
  43. 43.
    Hesse M, Frohlich LF, Zeitz U et al. Ablation of vitamin D signaling rescues bone, mineral and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 2007; 26(2):75–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Ohnishi M, Nakatani T, Lanske B et al. In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin d levels. Circ Cardiovasc Genet 2009; 2(6):583–590.PubMedCrossRefGoogle Scholar
  45. 45.
    Stubbs JR, Liu S, Tang W et al. Role of Hyperphosphatemia and 1,25-Dihydroxyvitamin D in Vascular Calcification and Mortality in Fibroblastic Growth Factor 23 Null Mice. J Am Soc Nephrol 2007; 18(7):2116–2124.PubMedCrossRefGoogle Scholar
  46. 46.
    Morishita K, Shirai A, Kubota M et al. The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 2001; 131(12):3182–3188.PubMedGoogle Scholar
  47. 47.
    Kuroo M. A potential link between phosphate and aging—lessons from Klotho-deficient mice. Mech Ageing Dev 2010; 131(4):270–275.CrossRefGoogle Scholar
  48. 48.
    Brauer MJ, Huttenhower C, Airoldi EM et al. Coordination of growth rate, cell cycle, stress response and metabolic activity in yeast. Mol Biol Cell 2008; 19(1):352–367.PubMedCrossRefGoogle Scholar
  49. 49.
    Boer VM, de Winde JH, Pronk JT et al. The genome-wide transcriptional responses of Saccharomyces cerevisiae grown on glucose in aerobic chemostat cultures limited for carbon, nitrogen, phosphorus, or sulfur. J Biol Chem 2003; 278(5):3265–3274.PubMedCrossRefGoogle Scholar
  50. 50.
    Kurosu H, Yamamoto M, Clark JD et al. Suppression of Aging in Mice by the Hormone Klotho. Science 2005; 309(5742):1829–1833.PubMedCrossRefGoogle Scholar
  51. 51.
    Hu MC, Shi M, Zhang J et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010.Google Scholar
  52. 52.
    Kuro-o M. Klotho and aging. Biochim Biophys Acta 2009; 1790(10):1049–1058.PubMedCrossRefGoogle Scholar
  53. 53.
    Kestenbaum B, Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16(2):520–528.CrossRefGoogle Scholar
  54. 54.
    Chen CD, Podvin S, Gillespie E et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104(50):19796–19801.PubMedCrossRefGoogle Scholar
  55. 55.
    Bloch L, Sineshchekova O, Reichenbach D et al. Klotho is a substrate for alpha-, beta-and gamma-secretase. FEBS Lett 2009; 583(19):3221–3224.PubMedCrossRefGoogle Scholar
  56. 56.
    Imura A, Iwano A, Tohyama O et al. Secreted Klotho protein in sera and CSF: implication for posttranslational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565(1-3):143–147.PubMedCrossRefGoogle Scholar
  57. 57.
    Goetz R, Nakada Y, Hu MC et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci USA 2010; 107(1):407–412.PubMedCrossRefGoogle Scholar
  58. 58.
    Cha SK, Ortega B, Kurosu H et al. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci USA 2008; 105(28):9805–9810.PubMedCrossRefGoogle Scholar
  59. 59.
    Chang Q, Hoefs S, van der Kemp AW et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005; 310(5747):490–493.PubMedCrossRefGoogle Scholar
  60. 60.
    Cha SK, Hu MC, Kurosu H et al. Regulation of ROMK1 channel and renal K+ excretion by Klotho. Mol Pharmacol 2009; 76(1):38–46.PubMedCrossRefGoogle Scholar
  61. 61.
    Utsugi T, Ohno T, Ohyama Y et al. Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging. Metabolism 2000; 49(9):1118–1123.PubMedCrossRefGoogle Scholar
  62. 62.
    Salhanick AI, Amatruda JM. Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus. Am J Physiol 1988; 255(2 Pt 1):E173–E179.PubMedGoogle Scholar
  63. 63.
    Sasaki A, Hata K, Suzuki S et al. Overexpression of plasma membrane-associated sialidase attenuates insulin signaling in transgenic mice. J Biol Chem 2003; 278(30):27896–27902.PubMedCrossRefGoogle Scholar
  64. 64.
    Tatar M, Bartke A, Antebi A. The Endocrine Regulation of Aging by Insulin-like Signals. Science 2003; 299(5611):1346–1351.PubMedCrossRefGoogle Scholar
  65. 65.
    Ito S, Kinoshita S, Shiraishi N et al. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein. Mech Dev 2000; 98(1–2):115–119.CrossRefGoogle Scholar
  66. 66.
    Ito S, Fujimori T, Furuya A et al. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest 2005; 115(8):2202–2208.PubMedCrossRefGoogle Scholar
  67. 67.
    Yu C, Wang F, Kan M et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 2000; 275(20):15482–15489.PubMedCrossRefGoogle Scholar
  68. 68.
    Inagaki T, Choi M, Moschetta A et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2(4):217–225.PubMedCrossRefGoogle Scholar
  69. 69.
    Kurosu H, Choi M, Ogawa Y et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282(37):26687–26695.PubMedCrossRefGoogle Scholar
  70. 70.
    Lin BC, Wang M, Blackmore C et al. Liver-specific Activities of FGF19 Require Klotho beta. J Biol Chem 2007; 282(37):27277–27284.PubMedCrossRefGoogle Scholar
  71. 71.
    Wu X, Ge H, Gupte J et al. Co-receptor requirements for fibroblast growth factor-19 signaling. J Biol Chem 2007; 282(40):29069–29072.PubMedCrossRefGoogle Scholar
  72. 72.
    Ogawa Y, Kurosu H, Yamamoto M et al. betaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 2007; 104(18):7432–7437.PubMedCrossRefGoogle Scholar
  73. 73.
    Kharitonenkov A, Dunbar JD, Bina HA et al. FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho. J Cell Physiol 2007; 215(1):1–7.CrossRefGoogle Scholar
  74. 74.
    Kharitonenkov A, Shiyanova TL, Koester A et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6):1627–1635.PubMedCrossRefGoogle Scholar
  75. 75.
    Inagaki T, Dutchak P, Zhao G et al. Endocrine Regulation of the Fasting Response by PPARalpha-Mediated Induction of Fibroblast Growth Factor 21. Cell Metab 2007; 5(6):415–425.PubMedCrossRefGoogle Scholar
  76. 76.
    Ito S, Fujimori T, Hayashizaki Y et al. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim Biophys Acta 2002; 1576(3):341–345.PubMedGoogle Scholar
  77. 77.
    Tacer KF, Bookout AL, Ding X et al. Comprehensive Expression Atlas of the Fibroblast Growth Factor System in Adult Mouse. Mol Endocrinol 2010; In press.Google Scholar
  78. 78.
    Shimada T, Mizutani S, Muto T et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98(11):6500–6505.PubMedCrossRefGoogle Scholar
  79. 79.
    Bai XY, Miao D, Goltzman D et al. The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 2003; 278(11):9843–9849.PubMedCrossRefGoogle Scholar
  80. 80.
    Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289(1):F8–28.PubMedCrossRefGoogle Scholar
  81. 81.
    Goodwin B, Jones SA, Price RR et al. A regulatory cascade of the nuclear receptors FXR, SHP-1 and LRH-1 represses bile acid biosynthesis. Mol Cell 2000; 6(3):517–526.PubMedCrossRefGoogle Scholar
  82. 82.
    Lu TT, Makishima M, Repa JJ et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 2000; 6(3):507–515.PubMedCrossRefGoogle Scholar
  83. 83.
    Kalaany NY, Mangelsdorf DJ. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 2006; 68:159–191.PubMedCrossRefGoogle Scholar
  84. 84.
    Kuipers F, Stroeve JH, Caron S et al. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Curr Opin Lipidol 2007; 18(3):289–297.PubMedCrossRefGoogle Scholar
  85. 85.
    Badman MK, Pissios P, Kennedy AR et al. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARalpha and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metab 2007; 5(6):426–437.PubMedCrossRefGoogle Scholar
  86. 86.
    Lefebvre P, Chinetti G, Fruchart JC et al. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006; 116(3):571–580.PubMedCrossRefGoogle Scholar
  87. 87.
    Kersten S, Seydoux J, Peters JM et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. journal of clinical investigation 1999; 103(11):1489–1498.PubMedCrossRefGoogle Scholar
  88. 88.
    Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000; 405(6785):421–424.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Makoto Kuro-o
    • 1
  1. 1.Department of PathologyUniversity of Texas Southwestern Medical Center at DallasDallasUSA

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