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

• RESULTS: Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes [13].
• We conclude that PA and RBP are useful measures of protein repletion in critically ill infants requiring parenteral nutrition [14].
• The retinol and retinyl ester concentrations in human xenografted squamous cell carcinomas, with various concentrations of cellular retinol-binding protein (CRBP), were studied, as well as the in vivo uptake and esterification in these tumours of labelled retinol, presented as a complex with plasma RBP [15].
• However, molecular-exclusion HPLC may be able to distinguish increases in RBP concentration associated with renal failure from those caused by altered vitamin A status, because renal failure causes abnormalities in the number and retention times of chromatographic peaks as well as their areas [16].
• We hypothesize that the loss of CRBP1 and RBP expression disrupts retinol metabolism and retinoic acid production, which may facilitate the occurrence of genetic damage leading to the malignant transformation of the ovarian surface epithelium, the cells from which ovarian cancer arises [17].
• Plasma RBP4 levels were associated with SCH independent of obesity in elderly subjects with normal glucose tolerance, indicating that RBP4 level could be used as an index of CVD risk in SCH [18].

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

• Studies in mice suggest that adipocytes serve as glucose sensors and regulate systemic glucose metabolism through release of serum retinol-binding protein 4 (RBP4) [1].
• Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels [13].
• The complex of retinol with its carrier protein, retinol-binding protein (RBP) has been crystallized and its three-dimensional structure determined using X-ray crystallography [22].
• In plasma the thyroid hormone-binding protein transthyretin (TTR) forms a tight complex with the specific retinol carrier retinol-binding protein (RBP) [4].
• Retinol-binding protein (RBP) is the specific blood carrier for the transport of retinol (vitamin A) to target tissues [23].
• In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol [24].
• The increase in RBP4 mRNA after pioglitazone treatment is unusual, suggesting a complex regulation of this novel adipokine [25].
• Rosiglitazone treatment in patients with diabetes resulted in a lower serum RBP4 level (35.2 +/- 10.2 vs. 24.9 +/- 5.6 microg/ml, before vs. after treatment) [26].
• The association of RBP-4 and adiponectin with insulin sensitivity was age, sex, and body mass index independent, but stepwise regression analysis suggested that RBP-4, but not adiponectin and leptin, was independently associated with insulin sensitivity [27].
• In multiple linear regression analyses adjusted to age, gender, and pubertal stage, RBP4 was significantly correlated to insulin and body mass index [28].
• We conclude that the mechanism for the insulin-sensitizing effects of exercise could involve increased adiponectin and reduced RBP4 levels in exercise-trained women [29].

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

• Venous glucose concentrations were similar throughout oral glucose tolerance testing, and basal RBP4 expression in adipose tissue and serum RBP4 concentrations were similar in the groups with higher and lower interstitial glucose levels [1].
• Retinol-binding protein from nonkeratinizing human oral mucosa showed different immunoblotting patterns when compared to epidermal RBP [35].
• Complex formation prevents extensive loss of RBP through glomerular filtration, and the loss of Leu-182 and Leu-183 would result in a decreased affinity of RBP for TTR [36].
• In the present study, we have purified RBP using a simple method, which involves (NH(4))(2)SO(4) fractionation followed by sequential gel filtration under native conditions and 6 M urea [37].
• RESEARCH DESIGN AND METHODS: An enzyme-linked immunosorbent assay was developed to measure human RBP4 plasma concentrations, which were then compared with various parameters related to insulin resistance in subjects with normal glucose tolerance (NGT; n = 57), impaired glucose tolerance (IGT; n = 48), and type 2 diabetes (n = 49) [38].

References