Horm Metab Res 2006; 38(4): 269-278
DOI: 10.1055/s-2006-925349
Review
© Georg Thieme Verlag KG Stuttgart · New York

The Retinol-binding Protein System: A Potential Paradigm for Steroid-binding Globulins?

C.  Redondo1 , B.  J.  Burke1 , J.  B. C.  Findlay1
  • 1 Department of Biochemistry and Microbiology, University of Leeds, United Kingdom
Further Information

Publication History

Received 23 September 2005

Accepted after revision 10 November 2005

Publication Date:
15 May 2006 (online)

Abstract

Retinol (vitamin A) is an example of a small molecule that is essential for higher organisms; its utilisation has been involved in the evolution of a number of proteins. In mammalian species, retinol is obtained from the diet and controls the release of its binding protein from hepatocytes into the blood stream. Subsequent influx into cells under normal situations usually involves a specific membrane-bound receptor for retinol-binding protein, which facilitates the uptake of retinol alone or bound to its carrier. This specific receptor has not yet been identified, but a receptor for a related lipocalin has been cloned. It represents a relatively new family, and there are a number of related genes in various eukaryotic genomes, suggesting that the system is very widespread in multicellular organisms. Its significance has been highlighted recently by the suggestion that retinol-binding protein, through its receptor, may play a major role in type 2 diabetes, perhaps the greatest scourge of modern society. This system may provide a new paradigm in mammalian biology, another example of which may exist in the processes responsible for steroid handling. This review outlines the characteristics of retinol utilisation in mammalian species, focusing primarily on the uptake system.

References

  • 1 Watson C S, Gametchu B. Proteins of multiple classes may participate in nongenomic steroid actions.  Exp Biol Med (Maywood). 2003;  228(11) 1272-1281
  • 2 de Wolf F A, Brett G M. Ligand-binding proteins: their potential for application in systems for controlled delivery and uptake of ligands.  Pharmacol Rev. 2000;  52(2) 207-236
  • 3 Gottesman M E, Quadro L, Blaner W S. Studies of vitamin A metabolism in mouse model systems.  Bioessays. 2001;  23(5) 409-419
  • 4 Noy N, Xu Z J. Interactions of retinol with binding proteins: implications for the mechanism of uptake by cells.  Biochemistry. 1990;  29(16) 3878-3883
  • 5 Sivaprasadarao A, Findlay J B. The interaction of retinol-binding protein with its plasma-membrane receptor.  Biochem J. 1988;  255(2) 561-569
  • 6 Sivaprasadarao A, Findlay J B. The mechanism of uptake of retinol by plasma-membrane vesicles.  Biochem J. 1988;  255(2) 571-579
  • 7 Shingleton J L, Skinner M K, Ong D E. Characteristics of retinol accumulation from serum retinol-binding protein by cultured Sertoli cells.  Biochemistry. 1989;  28 9641-9647
  • 8 Senoo H, Smeland S, Malaba L, Bjerknes T, Stang E, Roos N, Berg T, Norum K R, Blomhoff R. Transfer of retinol-binding protein from HepG2 human hepatoma cells to co-cultured rat stellate cells.  Proc Natl Acad Sci USA. 1993;  90 3616-3620
  • 9 Davis J T, Ong D E. Retinol processing by the peritubular cell from rat testis.  Biol Reprod. 1995;  52 356-364
  • 10 Pfeffer B A, Clark V M, Flannery J G, Bok D. Membrane receptors for retinol-binding protein in cultured human retinal pigment epithelium. Invest.  Ophthalmol Vis Sci. 1986;  27 1031-1040
  • 11 Bavik C O, Eriksson U, Allen R A, Peterson P A. Identification and partial characterization of a retinal pigment epithelial membrane receptor for plasma retinol-binding protein.  J Biol Chem. 1991;  266 14 978-14 985
  • 12 Eriksson U, Hansson E, Nilsson M, Jonsson K H, Sundelin J, Peterson P A. Increased levels of several retinoid binding proteins resulting from retinoic acid-induced differentiation of F9 cells.  Cancer Res. 1986;  46 717-722
  • 13 MacDonald P N, Bok D, Ong D E. Localization of cellular retinol-binding protein and retinol-binding protein in cells comprising the blood-brain barrier of rat and human.  Proc Natl Acad Sci USA,. 1990;  87 4265-4269
  • 14 Nakhla A M, Leonard J, Hryb D J, Rosner W. Sex hormone-binding globulin receptor signal transduction proceeds via a G protein.  Steroids. 1999;  64 213-216
  • 15 Maitra U S, Khan M S, Rosner W. Corticosteroid-binding globulin receptor of the rat hepatic membrane: solubilization, partial characterization, and the effect of steroids on binding.  Endocrinol. 1993;  133 1817-1822
  • 16 Yang Q, Graham T E, Mody N, Preitner F, Peroni O F, Zabolotny J M, Kotani K, Quadro L, Kahn B B. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.  Nature. 2005;  436(7049) 356-562
  • 17 Heller J. Transport of retinol to ocular tissues. An overview.  World Rev Nutr Diet. 1978;  31 42-44
  • 18 Futterman S, Heller J. The enhancement of fluorescence and the decreased susceptibility to enzymatic oxidation of retinol complexed with bovine serum albumin, β -lactoglobulin, and the retinol-binding protein of human plasma.  J Biol Chem. 1972;  247(16) 5168-5172
  • 19 Horwitz J, Heller J. Interactions of all-trans, 9-, 11-, and 13-cis-retinal, all-trans-retinyl acetate, and retinoic acid with human retinol-binding protein and prealbumin.  J Biol Chem. 1973;  248(18) 6317-6324
  • 20 Heller J, Horwitz J. Conformational changes following interaction between retinol isomers and human retinol-binding protein and between the retinol-binding protein and prealbumin.  J Biol Chem. 1973;  248(18) 6308-6316
  • 21 Heller J, Horwitz J. The binding stoichiometry of human plasma retinol-binding protein to prealbumin.  J Biol Chem. 1974;  249(18) 5933-5938
  • 22 Heller J, Horwitz J. Interactions of retinol-binding protein with various chromophores and with thyroxine-binding protein. A model for visual pigments.  Exp Eye Res. 1974;  18(1) 41-49
  • 23 Bok D, Heller J. Transport of retinol from the blood to the retina: an autoradiographic study of the pigment epithelial cell surface receptor for plasma retinol-binding protein.  Exp Eye Res. 1976;  22(5) 395-402
  • 24 Chen C C, Heller J. Uptake of retinol and retinoic acid from serum retinol-binding protein by retinal pigment epithelial cells.  J Biol Chem. 1977;  252(15) 5216-5221
  • 25 Ong D E. Cellular transport, and metabolism of vitamin A: role of the cellular retinoid-binding proteins.  Nutr Rev. 1994;  52 24-31
  • 26 Ette S I, Basu T K, Dickerson J WT. Short-term effect of zinc sulfate on plasma and hepatic concentrations of vitamins A and E in normal weanling rats.  Nutr Metab. 1979;  23 11-16
  • 27 Olson J A. Benefits and liabilities of vitamin A and carotenoids.  J Nutr. 1996;  126 (4 Suppl) 1208-1212
  • 28 Bonet M L, Ribot J, Felipe F, Palou A. Vitamin A and the regulation of fat reserves.  Cell Mol Life Sci. 2003;  60(7) 1311-1321
  • 29 Tsutsumi C, Okuno M, Tannous L, Piantedosi R, Allan M, Goodman D S, Blaner W S. Retinoids and retinoid-binding protein expression in rat adipocytes.  J Biol Chem. 1992;  267(3) 1805-1810
  • 30 Harrison E H. Mechanisms of digestion and absorption of dietary vitamin A.  Annu Rev Nutr. 2005;  25 7-103
  • 31 Soprano D R, Blaner W S. Plasma retinol-binding protein. In: Sporn MB, Roberts AB, Goodman DS. (eds.) The retinoids: biology, chemistry and medicine. 2nd ed. New York; Raven Press 1994: 257-282
  • 32 Blomhoff R. Overview of vitamin A: metabolism and function. In: Blomhoff, R. (ed.) Vitamin A in health and disease. New York; Marcel Dekker 1994: 1-35
  • 33 Goodman D S. Plasma retinol-binding protein. In: Sporn, MB, Roberts, AB Goodman, DS (eds.) The Retinoids, vol. 2. 1984 New York; Academic Press 41-88
  • 34 Ingenbleek Y, Young V. Transthyretin (prealbumin) in health and disease: Nutritional implications.  Annual Review of Nutrition. 1994;  14 495-533
  • 35 Bellovino D, Morimoto T, Tosetti F, Gaetani S. Retinol-binding protein and transthyretin are secreted as a complex formed in the endoplasmic reticulum in HepG2 human hepatocarcinoma cells.  Exp Cell Res. 1996;  222 77-83
  • 36 Mehlus H, Nilsson T, Peterson P A, Rask L. Retinol-binding protein and transthyretin expressed in Hela cells form a complex in the endoplasmic reticulum both in the absence and in the presence of retinol.  Exp Cell Res. 1991;  197 119-124
  • 37 Newcomer M E, Ong D E. Plasma retinol binding protein: structure and function of the prototypic lipocalin.  Biochim Biophys Acta. 2000;  1482(1 - 2) 57-64
  • 38 Sundaram M, Sivaprasadarao A, DeSousa M M, Findlay J B. The transfer of retinol from serum retinol-binding protein to cellular retinol-binding protein is mediated by a membrane receptor.  J Biol Chem. 1998;  273 3336-3342
  • 39 Zanotti G, Marcello M, Malpeli G, Folli C, Sartori G, Berni R. Crystallographic studies on complexes between retinoids and plasma retinol-binding protein.  J Biol Chem. 1994;  269(47) 29 613-29 620
  • 40 Hathcock J N, Hattan D G, Jenkins M Y, McDonald J T, Sundaresan P R, Wilkening V L. Evaluation of vitamin A toxicity.  Am J Clin Nutr. 1990;  52 183-202
  • 41 Tanumihardjo S A. Functions and actions of retinoids and carotenoids: building the vision of James Allen Olson.  Am Soc Nutr Sci. 2004;  290S-293S
  • 42 Dixon J L, DS G oodman. Studies on the metabolism of retinol-binding protein by primary hepatocytes from retinol-deficient rats.  J Cell Physiol. 1987;  130 14-20
  • 43 Perozzi G, Mengheri E, Colantuoni V, Gaetani S. Vitamin A intake and in vivo expression of the genes involved in retinol transport.  Eur J Biochem. 1991;  196 211-217
  • 44 Christian P, West K P Jr. Interactions between zinc and vitamin A: an update.  Am J Clin Nutr. 1998;  68 435S-441S
  • 45 Kanai M, Raz A, Goodman D. Retinol binding protein: the transport protein for vitamin A in human plasma.  J Clin Invest. 1968;  47 2025-2044
  • 46 Newcomer M E, Ong D E. Plasma retinol binding protein: structure and function of the prototypic lipocalin.  Biochim Biophys Acta. 2000;  1482(1 - 2) 57-64
  • 47 Bellovino D, Apreda M, Gragnoli S, Massimi M, Gaetani S. Vitamin A transport: in vitro models for the study of RBP secretion.  Molecular Aspects of Medicine. 2003;  24 411-420
  • 48 Newcomer M E, Jones T A, Aqvist J, Sundelin J, Eriksson U, Rask L, Peterson P A. The three-dimensional structure of retinol-binding protein.  EMBO J. 1984;  3(7) 1451-1454
  • 49 Cowan S W, Newcomer M E, Jones T A. Crystallographic refinement of human serum retinol binding protein at 2A resolution.  Proteins. 1990;  8(1) 44-61
  • 50 Zanotti G, Ottonello S, Berni R, Monaco H L. Crystal structure of the trigonal form of human plasma retinol-binding protein at 2.5 A resolution.  J Mol Biol. 1993;  230(2) 613-624
  • 51 Zanotti G, Berni R, Monaco H L. Crystal structure of liganded and unliganded forms of bovine plasma retinol-binding protein.  J Biol Chem. 1993;  268(15) 10 728-10 738
  • 52 Zanotti G, Panzalorto M, Marcato A, Malpeli G, Folli C, Berni R. Structure of pig plasma retinol-binding protein at 1.65 A resolution.  Acta Crystallogr D Biol Crystallogr. 1998;  54(Pt 5) 1049-1052
  • 53 Zanotti G, Calderone V, Beda M, Malpeli G, Folli C, Berni R. Structure of chicken plasma retinol-binding protein.  Biochim Biophys Acta. 2001;  1550(1) 64-69
  • 54 Noy N, Slosberg E, Scarlata S. Interactions of retinol with binding proteins: studies with retinol-binding protein and with transthyretin.  Biochemistry. 1992;  31(45) 11 118-1124
  • 55 Sivaprasadarao A, Findlay J B. Structure-function studies on human retinol-binding protein using site-directed mutagenesis.  Biochem J. 1994;  300 437-442
  • 56 Newcomer M E. Retinoid-binding proteins: structural determinants important for function.  FASEB J. 1995;  9(2) 229-239
  • 57 Monaco H L. The transthyretin-retinol-binding protein complex.  Biochim Biophys Acta. 2000;  1482(1 - 2) 65-72
  • 58 Shidoji Y, Muto Y. Vitamin A transport in plasma of the non-mammalian vertebrates: isolation and partial characterisation of piscine retinol-binding-protein.  Journal of Lipid Research. 1977;  18 679-691
  • 59 Senoo H, Stang E, Nilsson A, Kindberg G M, Berg T, Roos N, Norum K R, Blomhoff R. Internalization of retinol-binding protein in parenchymal and stellate cells of rat liver.  J Lipid Res. 1990;  31(7) 1229-1239
  • 60 Matarese V, Lodish H F. Specific uptake of retinol-binding protein by variant F9 cell lines.  J Biol Chem. 1993;  268(25) 18 859-18 865
  • 61 Bavik C O, Busch C, Eriksson U. Characterization of a plasma retinol-binding protein membrane receptor expressed in the retinal pigment epithelium.  J Biol Chem. 1992;  267(32) 23 035-23 042
  • 62 Sivaprasadarao A, Boudjelal M, Findlay J B. Solubilization and purification of the retinol-binding protein receptor from human placental membranes.  Biochem J. 1994;  302( Pt 1) 245-251
  • 63 Sundaram M, van Aalten D M, Findlay J B, Sivaprasadarao A. The transfer of transthyretin and receptor-binding properties from the plasma retinol-binding protein to the epididymal retinoic acid-binding protein.  Biochem J. 2002;  362(Pt 2) 265-271
  • 64 Piantedosi R, Ghyselinck N, Blaner W S, Vogel S. Cellular retinol-binding protein type III is needed for retinoid incorporation into milk.  J Biol Chem. 2005;  280(25) 24 286-24 292
  • 65 Folli C, Calderone V, Ramazzina I, Zanotti G, Berni R. Ligand binding and structural analysis of a human putative cellular retinol-binding protein.  J Biol Chem. 2002;  277(44) 41 970-41 977
  • 66 Matt N, Schmidt C K, Dupe V, Dennefeld C, Nau H, Chambon P, Mark M, Ghyselinck N B. Contribution of cellular retinol-binding protein type 1 to retinol metabolism during mouse development.  Dev Dyn. 2005;  233(1) 167-176
  • 67 Noy N. Retinoid-binding proteins: mediators of retinoid action.  Biochem J. 2000;  348 (Pt 3) 481-495
  • 68 Weiler R, Pottek M, Schultz K, Janssen-Bienhold U. Retinoic acid, a neuromodulator in the retina.  Prog Brain Res. 2001;  131 309-318
  • 69 Cowan S W, Newcomer M E, Jones T A. Crystallographic studies on a family of cellular lipophilic transport proteins. Refinement of P2 myelin protein and the structure determination and refinement of cellular retinol-binding protein in complex with all-trans-retinol.  J Mol Biol. 1993;  230(4) 1225-1246
  • 70 Tosetti F, Ferrari N, Pfeffer U, Brigati C, Vidali G. Regulation of plasma retinol binding protein secretion in human HepG2 cells.  Exp Cell Res. 1992;  200 467-472
  • 71 Bellovino D, Lanyau Y, Garaguso I, Amicone L, Cavallari C, Tripodi M, Gaetani S. MMH cells: An in vitro model for the study of retinol-binding protein secretion regulated by retinol.  J Cell Physiol. 1999;  181(1) 24-32
  • 72 Quadro L, Blaner W S, Salchow D J, Vogel S, Piantedosi R, Gouras P, Freeman S, Cosma M P, Colantuoni V, Gottesman M E. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein.  EMBO J. 1999;  18(17) 4633-4644
  • 73 Quadro L, Blaner W S, Hamberger L, van Gelder R N, Vogel S, Piantedosi R, Gorras P, Colantuoni V, Gottesman M E. Muscle expression of human retinol-binding protein (RBP). Suppression of the visual defect of RBP knockout mice.  J Biol Chem. 2002;  277(33) 30 191-30 197
  • 74 Quadro L, Hamberger L, Colantuoni V, Gottesman M E, Blaner W S. Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models.  Mol Aspects Med. 2003;  24(6) 421-430
  • 75 Seeliger M W, Biesalski H K, Wissinger B, Gollnick H, Gielen S, Frank J, Beck S, Zrenner E. Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis.  Invest Ophthalmol Vis Sci. 1999;  40(1) 3-11
  • 76 Quadro L, Hamberger L, Gottesman M E, Wang F, Colantuoni V, Blaner W S, Mendelsohn C L. Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency.  Endocrinology. 2005;  146(10) 4479-4490
  • 77 Wojnar P, Lechner M, Merschak P, Redl B. Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display.  J Biol Chem. 2001;  276(23) 20 206-20 212
  • 78 Wojnar P, Lechner M, Redl B. Antisense down-regulation of lipocalin-interacting membrane receptor expression inhibits cellular internalization of lipocalin-1 in human NT2 cells.  J Biol Chem. 2003;  278(18) 16 209-16 215
  • 79 Redl B, Holzfeind P, Lottspeich F. cDNA cloning and sequencing reveals human tear prealbumin to be a member of the lipophilic-ligand carrier protein superfamily.  J Biol Chem. 1992;  267(28) 20 282-20 287
  • 80 Glasgow B J, Abduragimov A R, Farahbakhsh Z T, Faull K F, Hubbell W L. Tear lipocalins bind a broad array of lipid ligands.  Curr Eye Res. 1995;  14(5) 363-372
  • 81 Briand L, Eloit C, Nespoulous C, Bezirard V, Huet J C, Henry C, Blon F, Trotier D, Pernollet J C. Evidence of an odorant-binding protein in the human olfactory mucus: location, structural characterization, and odorant-binding properties.  Biochemistry. 2002;  41(23) 7241-7252
  • 82 Gasymov O K, Abduragimov A R, Gasimov E O, Yusifov T N, Dooley A N, Glasgow B J. Tear lipocalin: potential for selective delivery of rifampin.  Biochim Biophys Acta. 2004;  1688(2) 102-111
  • 83 Fluckinger M, Haas H, Merschak P, Glasgow B J, Redl B. Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores.  Antimicrob Agents Chemother. 2004;  48(9) 3367-3372
  • 84 Holzfeind P, Redl B. Structural organization of the gene encoding the human lipocalin tear prealbumin and synthesis of the recombinant protein in Escherichia coli.  Gene. 1994;  139(2) 177-183
  • 85 Lechner M, Wojnar P, Redl B. Human tear lipocalin acts as an oxidative-stress-induced scavenger of potentially harmful lipid peroxidation products in a cell culture system.  Biochem J. 2001;  356 (Pt 1) 129-135
  • 86 Akerstrom B, Flower D R, Salier J P. Lipocalins: unity in diversity.  Biochim Biophys Acta. 2000;  1482(1 - 2) 1-8
  • 87 Goetz D H, Holmes M A, Borregaard N, Bluhm M E, Raymond K N, Strong R K. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition.  Mol Cell. 2000;  10(5) 1033-1043
  • 88 Loomis L D, Raymond K N. Solution equilibria of enterobactin and metal-enterobactin complexes.  Inorg Chem. 1991;  30 906-911
  • 89 Yang J, Goetz D, Li J Y, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J. An iron delivery pathway mediated by a lipocalin.  Mol Cell. 2002;  10(5) 1045-1056
  • 90 Collins J F, Franck C A, Kowdley K V, Ghishan F K. Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum.  Am J Physiol Gastrointest Liver Physiol. 2005;  288(5) 964-971
  • 91 Kushner P J, Hort E, Shine J, Baxter J D, Greene G L. Construction of cell lines that express high levels of the human estrogen receptor and are killed by estrogens.  Mol Endocrinol. 1990;  4(10) 1465-1473
  • 92 Watson C S, Pappas T C, Gametchu B. The other estrogen receptor in the plasma membrane: implications for the actions of environmental estrogens.  Environ Health Perspect. 1995;  103 (Suppl 7) 41-50

J. B. C. Findlay

Department of Biochemistry and Microbiology

University of Leeds · Mount Preston Road · LS2 9JT Leeds · United Kingdom

Fax: +44 (113) 343-3167

Email: j.b.c.findlay@leeds.ac.uk

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