Retinol binding protein 4 explained

Retinol binding protein 4, also known as RBP4, is a transporter protein^[1] for retinol (vitamin A alcohol). RBP4 has a molecular weight of approximately 21 kDa and is encoded by the RBP4 gene in humans.^{[2] [3]} It is mainly, though not exclusively, synthesized in the liver and circulates in the bloodstream as a hepatokine bound to retinol in a complex with transthyretin. RBP4 has been a drug target for ophthalmology research due to its role in vision.^[4] RBP4 may also be involved in metabolic diseases as suggested by recent studies.

Function

This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells.^[3]

Structure

RBP4 is a single polypeptide chain with a hydrophobic pocket where retinol binds. The RBP4-retinol complex then binds transthyretin in circulation to prevent renal filtration of RBP4.^[5]

In serum, TTR and RBP4 bind in a 1 to 1 stoichiometry (two molecules of TTR combine with two molecules of RBP4 to form a complex with a total molecular weight of approximately 80,000 daltons).^[6]

Clinical significance

Retinol-binding protein 4 has been a drug target for eye diseases as RBP4 is the sole carrier for retinol, which is an essential nutrient for the visual cycle. Animal studies using RBP4-antagonists showed that lowering RBP4 can lead to reduction in the accumulation of lipofuscin that leads to vision loss in eye diseases like Stargardt's disease and macular degeneration.^[7] An animal study using ABCA4 knockout mouse proved that reduction in serum RBP4 level could inhibit lipofuscin without inhibiting the visual cycle.[ref] One clinical study in age-related macular degeneration (AMD) was conducted using Fenretinide. The study showed trends in reducing lesion growth rate in AMD and rate of conversion from early stage AMD (dry AMD) to late stage AMD (wet AMD) without serious side effects.

RBP4 has recently been described as an adipokine that contributes to insulin resistance and diabetes in the AG4KO mouse model.^[8] In addition to the liver, RBP4 is also secreted by adipocytes of the fat tissue in a smaller portion and acts as a signal to surrounding cells, when there is a decrease in plasma glucose concentration.^[9] It is suspected that an elevated level of RBP4 attracts macrophages to the fat tissue, causes local inflammation, and leads to insulin resistance.^{[10] [11]}

Mutations in the RBP4 gene have recently been linked to a form of autosomal dominant microphthalmia, anophthalmia, and coloboma (MAC) disease.^[12] A unique feature of this disease is the maternal inheritance effect, when a fetus inherits a mutated copy of the RBP4 gene from its mother, but not from its father. The physiologic basis lies in pregnancy whereby the mutated gene product, retinol binding protein (RBP), has negative effects in transferring vitamin A from maternal liver storage sites to the placenta, and then again on the fetal circulation side when delivering vitamin A from the placenta to developing fetal tissues, most notably the developing eye. This 'double whammy' effect does not exist when the mutant RBP4 gene is inherited from the father. The above mechanism is separate from previously known types of maternal inheritance effects such as genomic imprinting, mitochondrial inheritance, or maternal oocyte mRNA transfer. The authors of the above study cite the potential of vitamin A supplementation in pregnant females who are known to carry an RBP4 mutation with retinyl ester which utilizes an RBP-independent pathway to deliver retinoids from the maternal intestines directly to the placenta and ultimately is uptaken by the fetus. The key would be to supplement during the first several months of life when the eye begins to develop, as supplementing later in pregnancy would be too late to avoid any potential MAC disease.

See also

• Retinol
• Adipokine
• Transthyretin (TTR)

Further reading

• Quadro L, Hamberger L, Colantuoni V, Gottesman ME, Blaner WS . Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models . Molecular Aspects of Medicine . 24 . 6 . 421–30 . December 2003 . 14585313 . 10.1016/S0098-2997(03)00038-4 .
• Newcomer ME, Ong DE . Plasma retinol binding protein: structure and function of the prototypic lipocalin . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1482 . 1–2 . 57–64 . October 2000 . 11058747 . 10.1016/s0167-4838(00)00150-3 .
• Fex G, Hansson B . Retinol-binding protein from human urine and its interaction with retinol and prealbumin . European Journal of Biochemistry . 94 . 1 . 307–13 . February 1979 . 571335 . 10.1111/j.1432-1033.1979.tb12896.x .
• Rask L, Anundi H, Peterson PA . The primary structure of the human retinol-binding protein . FEBS Letters . 104 . 1 . 55–8 . August 1979 . 573217 . 10.1016/0014-5793(79)81084-4 . 8540537 . free .
• Fex G, Albertsson PA, Hansson B . Interaction between prealbumin and retinol-binding protein studied by affinity chromatography, gel filtration and two-phase partition . European Journal of Biochemistry . 99 . 2 . 353–60 . September 1979 . 574085 . 10.1111/j.1432-1033.1979.tb13263.x . free .
• Monaco HL, Zanotti G . Three-dimensional structure and active site of three hydrophobic molecule-binding proteins with significant amino acid sequence similarity . Biopolymers . 32 . 4 . 457–65 . April 1992 . 1623143 . 10.1002/bip.360320425 . 34994569 .
• Cowan SW, Newcomer ME, Jones TA . Crystallographic refinement of human serum retinol binding protein at 2A resolution . Proteins . 8 . 1 . 44–61 . 1990 . 2217163 . 10.1002/prot.340080108 . 21613341 .
• D'Onofrio C, Colantuoni V, Cortese R . Structure and cell-specific expression of a cloned human retinol binding protein gene: the 5'-flanking region contains hepatoma specific transcriptional signals . The EMBO Journal . 4 . 8 . 1981–9 . August 1985 . 2998779 . 554451 . 10.1002/j.1460-2075.1985.tb03881.x.
• Pfeffer BA, Clark VM, Flannery JG, Bok D . Membrane receptors for retinol-binding protein in cultured human retinal pigment epithelium . Investigative Ophthalmology & Visual Science . 27 . 7 . 1031–40 . July 1986 . 3013795 .
• Kameko M, Ichikawa M, Katsuyama T, Kanai M, Kato M, Akamatsu T . Immunohistochemical localization of plasma retinol-binding protein and prealbumin in human pancreatic islets . The Histochemical Journal . 18 . 4 . 164–8 . April 1986 . 3525470 . 10.1007/BF01676116 . 2959823 .
• Siegenthaler G, Saurat JH . Loss of retinol-binding properties for plasma retinol-binding protein in normal human epidermis . The Journal of Investigative Dermatology . 88 . 4 . 403–8 . April 1987 . 3559267 . 10.1111/1523-1747.ep12469731 . free .
• Rask L, Vahlquist A, Peterson PA . Studies on two physiological forms of the human retinol-binding protein differing in vitamin A and arginine content . The Journal of Biological Chemistry . 246 . 21 . 6638–46 . November 1971 . 10.1016/S0021-9258(19)34162-6 . 5132677 . free .
• Colantuoni V, Romano V, Bensi G, Santoro C, Costanzo F, Raugei G, Cortese R . Cloning and sequencing of a full length cDNA coding for human retinol-binding protein . Nucleic Acids Research . 11 . 22 . 7769–76 . November 1983 . 6316270 . 326530 . 10.1093/nar/11.22.7769 .
• Newcomer ME, Jones TA, Aqvist J, Sundelin J, Eriksson U, Rask L, Peterson PA . The three-dimensional structure of retinol-binding protein . The EMBO Journal . 3 . 7 . 1451–4 . July 1984 . 6540172 . 557543 . 10.1002/j.1460-2075.1984.tb01995.x.
• Rask L, Anundi H, Böhme J, Eriksson U, Ronne H, Sege K, Peterson PA . Structural and functional studies of vitamin A-binding proteins . Annals of the New York Academy of Sciences . 359 . 79–90 . February 1981 . 1 . 6942701 . 10.1111/j.1749-6632.1981.tb12739.x . 1981NYASA.359...79R . 5781208 .
• Jaconi S, Rose K, Hughes GJ, Saurat JH, Siegenthaler G . Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure . Journal of Lipid Research . 36 . 6 . 1247–53 . June 1995 . 10.1016/S0022-2275(20)41132-0 . 7666002 . free .
• Berni R, Malpeli G, Folli C, Murrell JR, Liepnieks JJ, Benson MD . The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein . The Journal of Biological Chemistry . 269 . 38 . 23395–8 . September 1994 . 10.1016/S0021-9258(17)31527-2 . 8089102 . free .
• Seeliger MW, Biesalski HK, 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 . Investigative Ophthalmology & Visual Science . 40 . 1 . 3–11 . January 1999 . 9888420 .

Notes and References

1. Rask L, Anundi H, Fohlman J, Peterson PA . The complete amino acid sequence of human serum retinol-binding protein . Upsala Journal of Medical Sciences . 92 . 2 . 115–46 . 1987 . 2444024 . 10.3109/03009738709178685 . free .
2. Rocchi M, Covone A, Romeo G, Faraonio R, Colantuoni V . Regional mapping of RBP4 to 10q23----q24 and RBP1 to 3q21----q22 in man . Somatic Cell and Molecular Genetics . 15 . 2 . 185–90 . March 1989 . 2928844 . 10.1007/BF01535081 . 37896530 .
3. Web site: Entrez Gene: RBP4 retinol binding protein 4, plasma.
4. Cioffi CL, Dobri N, Freeman EE, Conlon MP, Chen P, Stafford DG, Schwarz DM, Golden KC, Zhu L, Kitchen DB, Barnes KD, Racz B, Qin Q, Michelotti E, Cywin CL, Martin WH, Pearson PG, Johnson G, Petrukhin K . Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease . EN . Journal of Medicinal Chemistry . 57 . 18 . 7731–57 . September 2014 . 25210858 . 4174998 . 10.1021/jm5010013 .
5. Kanai M, Raz A, Goodman DS . Retinol-binding protein: the transport protein for vitamin A in human plasma . The Journal of Clinical Investigation . 47 . 9 . 2025–44 . September 1968 . 5675424 . 297364 . 10.1172/jci105889 .
6. Naylor HM, Newcomer ME . The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP . Biochemistry . 38 . 9 . 2647–53 . March 1999 . 10052934 . 10.1021/bi982291i .
7. Radu RA, Han Y, Bui TV, Nusinowitz S, Bok D, Lichter J, Widder K, Travis GH, Mata NL . Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases . Investigative Ophthalmology & Visual Science . 46 . 12 . 4393–401 . December 2005 . 16303925 . 10.1167/iovs.05-0820 . free .
8. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB . Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes . Nature . 436 . 7049 . 356–62 . July 2005 . 16034410 . 10.1038/nature03711 . 2005Natur.436..356Y . 4343960 .
9. Herman MA, Kahn BB . Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony . The Journal of Clinical Investigation . 116 . 7 . 1767–75 . July 2006 . 16823474 . 1483149 . 10.1172/JCI29027 .
10. Moraes-Vieira PM, Yore MM, Dwyer PM, Syed I, Aryal P, Kahn BB . RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance . Cell Metabolism . 19 . 3 . 512–26 . March 2014 . 24606904 . 4078000 . 10.1016/j.cmet.2014.01.018 .
11. Galic S, Oakhill JS, Steinberg GR . Adipose tissue as an endocrine organ . Molecular and Cellular Endocrinology . 316 . 2 . 129–39 . March 2010 . 19723556 . 10.1016/j.mce.2009.08.018 . 7385199 .
12. Chou CM, Nelson C, Tarlé SA, Pribila JT, Bardakjian T, Woods S, Schneider A, Glaser T . Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease . Cell . 161 . 3 . 634–646 . April 2015 . 25910211 . 4409664 . 10.1016/j.cell.2015.03.006 .