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Gene Review

RBP4  -  retinol binding protein 4, plasma

Homo sapiens

Synonyms: PRBP, PRO2222, Plasma retinol-binding protein, RBP, Retinol-binding protein 4
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Disease relevance of RBP4

  • Five percent weight loss slightly decreased adipose RBP4 expression but did not influence circulating RBP4 [1].
  • In contrast to the animal data, RBP4 mRNA was downregulated in subcutaneous adipose tissue of obese women, and circulating RBP4 concentrations were similar in normal weight, overweight, and obese women (n = 74) [1].
  • RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD [2].
  • The 5'-flanking region of the RBP gene was fused upstream to the coding sequence of the bacterial enzyme chloramphenicol acetyl transferase (CAT): the chimeric gene was introduced, by calcium phosphate precipitation, into the human hepatoma cell line Hep G2 and into HeLa cells [3].
  • Therefore, in general a substantially altered binding of TTR to RBP is not associated with familial amyloidotic polyneuropathy [4].
  • The precise reason for elevated levels of RBP4 in overweight PCOS women is unknown, but it appears that 17beta-estradiol may play a role in their regulation in adipose tissue [5].
  • Women with gestational diabetes had lower RBP4 EIA and western blot levels than controls (median 6.8 [interquartile range, 3.9-14.3] vs 11.3 [7.8-19.9] microg/ml, p < 0.001 and 25.1 [21.7-29.6] vs 26.6 [23.5-32.2] microg/ml, p = 0.026) [6].

Psychiatry related information on RBP4

  • To evaluate possible effects of alcohol consumption on vitamin A and retinol-binding protein (RBP) status, baboons were pair-fed a nutritionally adequate liquid diet containing 50% of total calories either as ethanol or isocaloric carbohydrate [7].

High impact information on RBP4

  • Much is known now about the chemical structure, metabolism, and biologic roles of RBP, RBP delivers retinol to peripheral target tissues; delivery may involve cell surface receptors for RBP [8].
  • In 23 patients with chronic glomerulonephritis (CGN), in 9 with proximal tubular dysfunction (PTD), in 23 with various renal diseases (VRD), and in 10 with malignant lymphoma, the plasma level and the urinary excretion were compared with those of albumin (mol wt 67,000) and of the retinol-binding protein (RBP, mol wt 21,000) [9].
  • On a normal diet the patient was able to mobilize hepatic vitamin A, as indicated 71 days later by a repeat biopsy of the liver, which then contained 9000 IU of vitamin A/g. During this time his nutrition improved, serum vitamin A rose, and serum RBP became transiently saturated [10].
  • A stretch of DNA was constructed which carries two transcriptional units: 18 kb of the human retinol binding protein (RBP) gene, driving the expression of the bacterial chloramphenicol acetyl transferase, linked to 17.5 kb containing the entire A1AT coding sequence with additional 5' and 3' flanking sequences [11].
  • It has been found that 334 bases of the 5' flanking region of the human retinol-binding protein (RBP) gene contain sufficient information to direct accurate and specific transcription in human hepatoma but not in HeLa cells [12].

Chemical compound and disease context of RBP4


Biological context of RBP4

  • Experiments in mice suggest that elevated RBP4 levels cause insulin resistance [13].
  • Human plasma retinol binding protein (RBP) is coded by a single gene and is specifically synthesized in the liver [3].
  • We have characterized a lambda clone, from a human DNA library, carrying the gene coding for plasma RBP [3].
  • Two independent and equivalent RBP binding sites on recombinant normal TTR are characterized by a dissociation constant of about 0.4 microM [4].
  • RESULTS: Genomic DNA sequence analysis revealed 2 point mutations in the RBP gene: a T-to-A substitution at nucleotide 1282 of exon 3 and a G-to-A substitution at nucleotide 1549 of exon 4 [19].

Anatomical context of RBP4

  • RBP4 was highly expressed in isolated mature human adipocytes and secreted by differentiating human adipocytes [1].
  • RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable [1].
  • The human gene coding for RBP4 has been assigned to 10q23----24 using a panel of somatic cell hybrids and in situ hybridization experiments [20].
  • The experimental system consisted of the [3H]retinol-RBP complex, Escherichia coli-expressed recombinant apo-CRBP containing the 10 amino acid long streptavidin-binding peptide sequence at its C terminus (designated as CRBP-Strep) and permeabilized human placental membranes [21].
  • The hypothesis that the cellular uptake of retinol involves the specific interaction of a plasma membrane receptor with serum retinol-binding protein (RBP) at the extracellular surface followed by ligand transfer to cytoplasmic cellular retinol-binding protein (CRBP) has been investigated [21].

Associations of RBP4 with chemical compounds


Physical interactions of RBP4

  • Of particular interest, cellular retinol-binding protein 1 (CRBP1) and retinol-binding protein (RBP), two genes whose products are involved in retinol transport and metabolism, were found to be downregulated in this ovarian cancer model system [17].
  • Data are expressed as mean +/- S.E.M. RESULTS: Albumin and transferrin levels increased during convalescence to the normal range but pre-albumin and retinol binding protein (RBP) levels remained below normal for at least 24 months [30].

Regulatory relationships of RBP4

  • While TTR expressed alone was not retained intracellularly, TTR was retained in vitamin A-deficient cells when co-expressed with RBP [31].

Other interactions of RBP4

  • Multifactor dimensionality reduction indicated that the best genetic model for classical onset group versus controls involved the APCS gene, whereas for late-onset cases, one APCS variant (APCSv1) and two RBP variants (RBPv1 and RBPv2) are involved [32].
  • A nearly negligible affinity of the recombinant Ser-84 TTR for RBP was found [4].
  • The effects are specific: other binding proteins, including beta-lactoglobulin and serum albumin, despite their ability to bind retinol, failed to substitute for either RBP or apo-CRBP [21].
  • Weight loss (UBW) correlated with ALB (P less than 0.001), TBPA (P less than 0.005) and RBP (P less than 0.02) but did not correlate with TFN (P less than 0.06), TSF, and MAMC [33].
  • The plasma concentrations of retinol, retinol-binding protein (RBP), prealbumin, albumin, orosomucoid and alfa1-antitrypsin were also determined [34].

Analytical, diagnostic and therapeutic context of RBP4


  1. Retinol-binding protein 4 in human obesity. Janke, J., Engeli, S., Boschmann, M., Adams, F., B??hnke, J., Luft, F.C., Sharma, A.M., Jordan, J. Diabetes (2006) [Pubmed]
  2. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. Goodman, A.B. J. Cell. Physiol. (2006) [Pubmed]
  3. Structure and cell-specific expression of a cloned human retinol binding protein gene: the 5'-flanking region contains hepatoma specific transcriptional signals. D'Onofrio, C., Colantuoni, V., Cortese, R. EMBO J. (1985) [Pubmed]
  4. The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein. Berni, R., Malpeli, G., Folli, C., Murrell, J.R., Liepnieks, J.J., Benson, M.D. J. Biol. Chem. (1994) [Pubmed]
  5. Raised serum, adipocyte, and adipose tissue retinol-binding protein 4 in overweight women with polycystic ovary syndrome: effects of gonadal and adrenal steroids. Tan, B.K., Chen, J., Lehnert, H., Kennedy, R., Randeva, H.S. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  6. Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Krzyzanowska, K., Zemany, L., Krugluger, W., Schernthaner, G.H., Mittermayer, F., Schnack, C., Rahman, R., Brix, J., Kahn, B.B., Schernthaner, G. Diabetologia (2008) [Pubmed]
  7. Hepatic vitamin A depletion after chronic ethanol consumption in baboons and rats. Sato, M., Lieber, C.S. J. Nutr. (1981) [Pubmed]
  8. Overview of current knowledge of metabolism of vitamin A and carotenoids. Goodman, D.S. J. Natl. Cancer Inst. (1984) [Pubmed]
  9. Renal handling of Zn-alpha2-glycoprotein as compared with that of albumin and the retinol-binding protein. Ekman, R., Johansson, B.G., Ravnskov, U. J. Clin. Invest. (1976) [Pubmed]
  10. Reversible hepatotoxicity associated with hepatic vitamin A accumulation in a protein-deficient patient. Weber, F.L., Mitchell, G.E., Powell, D.E., Reiser, B.J., Banwell, J.G. Gastroenterology (1982) [Pubmed]
  11. Disruption of the LF-A1 and LF-B1 binding sites in the human alpha-1-antitrypsin gene has a differential effect during development in transgenic mice. Tripodi, M., Abbott, C., Vivian, N., Cortese, R., Lovell-Badge, R. EMBO J. (1991) [Pubmed]
  12. Negative control of liver-specific gene expression: cloned human retinol-binding protein gene is repressed in HeLa cells. Colantuoni, V., Pirozzi, A., Blance, C., Cortese, R. EMBO J. (1987) [Pubmed]
  13. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. Graham, T.E., Yang, Q., Blüher, M., Hammarstedt, A., Ciaraldi, T.P., Henry, R.R., Wason, C.J., Oberbach, A., Jansson, P.A., Smith, U., Kahn, B.B. N. Engl. J. Med. (2006) [Pubmed]
  14. Retinol-binding protein and prealbumin: useful measures of protein repletion in critically ill, malnourished infants. Helms, R.A., Dickerson, R.N., Ebbert, M.L., Christensen, M.L., Herrod, H.G. J. Pediatr. Gastroenterol. Nutr. (1986) [Pubmed]
  15. A relationship between retinol and cellular retinol-binding protein concentrations in human squamous cell carcinomas. Wahlberg, P., Fex, G., Wennerberg, J. Biochim. Biophys. Acta (1989) [Pubmed]
  16. Use of free and transthyretin-bound retinol-binding protein in serum as tests of vitamin A status in humans: effect of high creatinine concentrations in serum. Burri, B.J., Bankson, D.D., Neidlinger, T.R. Clin. Chem. (1990) [Pubmed]
  17. Decreased expression of retinol-binding proteins is associated with malignant transformation of the ovarian surface epithelium. Roberts, D., Williams, S.J., Cvetkovic, D., Weinstein, J.K., Godwin, A.K., Johnson, S.W., Hamilton, T.C. DNA Cell Biol. (2002) [Pubmed]
  18. Retinol binding protein-4 elevation is associated with serum thyroid-stimulating hormone level independently of obesity in elderly subjects with normal glucose tolerance. Choi, S.H., Lee, Y.J., Park, Y.J., Kim, K.W., Lee, E.J., Lim, S., Park, D.J., Kim, S.E., Park, K.S., Jang, H.C., Cho, B.Y. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  19. Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol binding protein. Biesalski, H.K., Frank, J., Beck, S.C., Heinrich, F., Illek, B., Reifen, R., Gollnick, H., Seeliger, M.W., Wissinger, B., Zrenner, E. Am. J. Clin. Nutr. (1999) [Pubmed]
  20. Regional mapping of RBP4 to 10q23----q24 and RBP1 to 3q21----q22 in man. Rocchi, M., Covone, A., Romeo, G., Faraonio, R., Colantuoni, V. Somat. Cell Mol. Genet. (1989) [Pubmed]
  21. The transfer of retinol from serum retinol-binding protein to cellular retinol-binding protein is mediated by a membrane receptor. Sundaram, M., Sivaprasadarao, A., DeSousa, M.M., Findlay, J.B. J. Biol. Chem. (1998) [Pubmed]
  22. The three-dimensional structure of retinol-binding protein. Newcomer, M.E., Jones, T.A., Aqvist, J., Sundelin, J., Eriksson, U., Rask, L., Peterson, P.A. EMBO J. (1984) [Pubmed]
  23. Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure. Jaconi, S., Rose, K., Hughes, G.J., Saurat, J.H., Siegenthaler, G. J. Lipid Res. (1995) [Pubmed]
  24. Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease. von Eynatten, M., Lepper, P.M., Liu, D., Lang, K., Baumann, M., Nawroth, P.P., Bierhaus, A., Dugi, K.A., Heemann, U., Allolio, B., Humpert, P.M. Diabetologia (2007) [Pubmed]
  25. Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone. Yao-Borengasser, A., Varma, V., Bodles, A.M., Rasouli, N., Phanavanh, B., Lee, M.J., Starks, T., Kern, L.M., Spencer, H.J., Rashidi, A.A., McGehee, R.E., Fried, S.K., Kern, P.A. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  26. Association of serum retinol-binding protein 4 and visceral adiposity in Chinese subjects with and without type 2 diabetes. Jia, W., Wu, H., Bao, Y., Wang, C., Lu, J., Zhu, J., Xiang, K. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  27. Serum retinol-binding protein-4, leptin, and adiponectin concentrations are related to ectopic fat accumulation. Perseghin, G., Lattuada, G., De Cobelli, F., Esposito, A., Belloni, E., Canu, T., Ragogna, F., Scifo, P., Del Maschio, A., Luzi, L. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  28. Retinol-binding protein 4 and its relation to insulin resistance in obese children before and after weight loss. Reinehr, T., Stoffel-Wagner, B., Roth, C.L. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  29. Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. Lim, S., Choi, S.H., Jeong, I.K., Kim, J.H., Moon, M.K., Park, K.S., Lee, H.K., Kim, Y.B., Jang, H.C. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  30. Recovery from the hepatic acute phase response in the severely burned and the effects of long-term growth hormone treatment. Thomas, S., Wolf, S.E., Chinkes, D.L., Herndon, D.N. Burns : journal of the International Society for Burn Injuries. (2004) [Pubmed]
  31. Retinol-binding protein and transthyretin expressed in HeLa cells form a complex in the endoplasmic reticulum in both the absence and the presence of retinol. Melhus, H., Nilsson, T., Peterson, P.A., Rask, L. Exp. Cell Res. (1991) [Pubmed]
  32. Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. Soares, M.L., Coelho, T., Sousa, A., Batalov, S., Conceição, I., Sales-Luís, M.L., Ritchie, M.D., Williams, S.M., Nievergelt, C.M., Schork, N.J., Saraiva, M.J., Buxbaum, J.N. Hum. Mol. Genet. (2005) [Pubmed]
  33. Plasma proteins as indices of response to nutritional therapy in cancer patients. Ota, D.M., Frasier, P., Guevara, J., Foulkes, M. Journal of surgical oncology. (1985) [Pubmed]
  34. Studies of cellular retinol-binding protein (CRBP) in squamous-cell carcinomas of the head and neck region. Fex, G., Wahlberg, P., Biörklund, A., Wennerberg, J., Willén, R. Int. J. Cancer (1986) [Pubmed]
  35. Loss of retinol-binding properties for plasma retinol-binding protein in normal human epidermis. Siegenthaler, G., Saurat, J.H. J. Invest. Dermatol. (1987) [Pubmed]
  36. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Naylor, H.M., Newcomer, M.E. Biochemistry (1999) [Pubmed]
  37. A new method for purification of human plasma retinol-binding protein and transthyretin. Raghu, P., Ravinder, P., Sivakumar, B. Biotechnol. Appl. Biochem. (2003) [Pubmed]
  38. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Cho, Y.M., Youn, B.S., Lee, H., Lee, N., Min, S.S., Kwak, S.H., Lee, H.K., Park, K.S. Diabetes Care (2006) [Pubmed]
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