Retinol-binding protein-4 (RBP4) is the carrier protein involved in the transport of retinol from the liver storage site to peripheral tissue.
NCBI Summary:
This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) 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. [provided by RefSeq, Jul 2008]
General function
Extracellular binding protein
Comment
Cellular localization
Secreted
Comment
Serum retinol-binding protein 4 levels in polycystic ovary syndrome. Lingaiah S et al. (2019) Serum levels of retinol-binding protein 4 (RBP4), an adipokine thought to effect systemic insulin sensitivity, were compared between women with polycystic ovary syndrome (PCOS) and non-PCOS controls to evaluate the association of RBP4 with clinical, hormonal and metabolic parameters of PCOS. Serum RBP4 levels were analysed in 278 women with PCOS (age range 18-57 years) and 191 non-PCOS controls (age 20-53 years) by enzyme-linked immunosorbent assay. Serum levels of RBP4 were increased in women with PCOS compared with control women in the whole population (45.1 ± 24.0 (SD) vs. 33.5 ± 18.3 mg/L, p<0.001). Age-stratified analysis showed that serum RBP4 levels were increased in women with PCOS aged ≤ 30 years compared with controls (47.7 ± 23.5 vs. 27.1 ± 10.4 mg/L, p<0.001), whereas no significant differences were seen in the other age groups. No significant correlations of RBP4 were seen with either steroids or indices of insulin resistance. Although serum RBP4 levels were increased in younger women with PCOS compared with age-matched non-PCOS controls, RBP4 does not seem to be a good marker of insulin resistance or other metabolic derangements in women with PCOS.//////////////////
Elevated serum RBP4 is associated with insulin resistance in women with polycystic ovary syndrome. Weiping L et al. (2007) Retinol binding protein 4 (RBP4) is a novel adipocyte-secreted protein that contributes to systemic insulin resistance. Experiments in mice suggest that elevated RBP4 causes insulin resistance. In the present study, we determined serum RBP4 concentration and evaluated its association with insulin resistance in women with polycystic ovarian syndrome (PCOS); 39 PCOS women and 45 healthy control subjects were enrolled in this study. Serum RBP4, fasting plasma glucose (FPG) and fasting serum insulin (FINS) were measured in all subjects. Furthermore, oral glucose tolerance test (OGTT), Botnia clamp (an intravenous glucose tolerance test followed by an euglycemic hyperinsulinemic clamp), and measurements of sex hormones were performed in 13 control subjects and all the PCOS women. The levels of serum RBP4 were elevated in PCOS women compared with the control (11.69 +/- 6.72 versus 7.75 +/- 5.96 microg/mL, p = 0.006). RBP4 levels were positively correlated with WHR (r = 0.216, p = 0.048), and intravenous glucose tolerance test beta cell index (IVGTT-beta index) which reflected beta cell function (r = 0.309, p = 0.028), but were inversely correlated with M value during Botnia clamp, which represented insulin sensitivity (r = -0.362, p = 0.008). No correlation was found between RBP4 and age, BMI, blood pressure, FPG, FINS, 2-h postprandial glucose, 2-h postprandial insulin, free testosterone, total testosterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH). In a linear stepwise regression analysis with a model including age, BMI, WHR, free testosterone, IVGTT-beta index, and M value as independent variables, only M value showed significant correlation with serum RBP4 levels (r2 = 0.105, f = 6.640, p = 0.012). In conclusion, serum RBP4 levels are significantly increased in PCOS women and associated with insulin resistance, which indicates that RBP4 may be a contributing factor linking adipose tissue with insulin resistance in PCOS.//////////////////
Ovarian function
Comment
The relationship between retinol-binding protein 4 levels, insulin resistance, androgen hormones and polycystic ovary syndrome. Mellati AA et al. Abstract Background. Retinol-binding protein 4 (RPB4), a 21-kDa peptide, is a recently identified adipokine that may contribute to the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to explore the association between serum RBP4 levels, androgen hormones and insulin resistance (IR) in women with PCOS. Methods. In this case-control study, 75 PCOS patients and 53 age- and body mass index (BMI)-matched control subjects referred to the Zanjan Metabolic Disease Research Center were enrolled. Serum RBP4 was measured using an enzyme-linked immunosorbent assay. BMI, waist circumference (WC), fasting levels of glucose, lipid profiles and insulin were also measured. A homeostatic model assessment of insulin resistance (HOMA-IR) value was used to determine the level of insulin resistance. Results. PCOS cases had significantly higher serum RBP4 and insulin levels than control subjects (44130 ? 12760 vs. 32980 ? 9560 ?g/L, p < 0.001, and 11790 ? 11480 vs. 7890 ? 4300 ?U/L, p < 0.05, respectively), in univariable analysis. RBP4 showed a positive correlation with serum testosterone (r = 0.62, p < 0.0001), dehydroepiandrosterone sulfate (r = 0.45, p < 0.0001) and the waist circumference (r = 0.37, p < 0.001) of PCOS patients but not with other measured clinical and biochemical variables. However, no correlation was observed between serum RBP4 levels and HOMA-IR in all studied subjects. A final logistic regression analysis demonstrated that testosterone and dehydroepiandrosterone sulfate are independently associated with PCOS. Conclusion. These findings indicate that RBP4 is not independently associated with PCOS. The elevation of RBP4 levels in PCOS women might be influenced by androgen hormones. Further prospective studies are needed to clarify molecular mechanisms.
Visfatin and retinol-binding protein 4 concentrations in lean, glucose-tolerant women with PCOS. Yildiz BO et al. Since insulin resistance is accepted to be a common feature of polycystic ovary syndrome (PCOS), the exact molecular mechanism(s) involved in glucose and lipid metabolism have been under investigation in the syndrome. Recently, two novel adipokines, namely visfatin and retinol-binding protein 4 (RBP4), have been suggested to play a role in insulin resistance and diabetes. This study sought to determine whether plasma concentrations of visfatin and RBP4 are altered in PCOS by comparing a total of 27 lean, normal glucose-tolerant PCOS patients with 19 age- and body mass index-matched healthy controls. The mean plasma visfatin concentrations were higher in PCOS patients than those in healthy subjects (37.9+/-18.2 versus 19.8+/-17.5, P<0.01), while RBP4 concentrations were similar between the two. Both adipokines were correlated with each other in the whole (r=0.50, P<0.01) and in PCOS (r=0.52, P<0.01) groups but not in controls. The results suggest that lean, glucose-tolerant women with PCOS have increased circulating visfatin and unaltered RBP4 concentrations compared with healthy lean women. In order to clarify overlapping effects and their potential contribution to the pathophysiology of PCOS, further studies are needed.
Expression regulated by
FSH
Comment
Regulation by FSH of the dynamic expression of retinol-binding protein 4 in the mouse ovary. Jiang Y et al. (2018) Ovarian retinoid homeostasis plays an important role in the physiological function of the ovary. Retinol-binding protein 4 (RBP4) acts as the mediator for the systemic and intercellular transport of retinol and is heavily involved in cellular retinol influx, efflux, and exchange. However, the expression patterns and regulatory mechanisms of Rbp4 in the ovary remain unclear. The expression pattern of ovarian Rbp4 was examined in immature mice during different developmental stages and in adult mice during different stages of the estrous cycle. The potential regulation and mechanisms of ovarian Rbp4 expression by estrogen and related gonadotropins in mouse ovaries were also investigated. The present study demonstrated that the ovarian expression of Rbp4 remained constant before puberty and increased significantly in the peripubertal period. In adult female mice, the expression of Rbp4 increased at proestrus and peaked at estrus at both the mRNA and protein levels. The protein distribution of RBP4 was mainly localized in the granulosa cell and theca cell layer in follicles. In addition, the expression of Rbp4 was significantly induced by follicle-stimulating hormone (FSH) or FSH + luteinizing hormone (LH) in combination in immature mouse (3 weeks old) ovaries in vivo and in granulosa cells cultured in vitro, both at the mRNA and protein levels. In contrast, treatment with LH or 17β-estradiol did not exhibit any observable effects on ovarian Rbp4 expression. Transcription factors high-mobility group AT-hook 1 (HMGA1), steroidogenic factor 1 (SF-1), and liver receptor homolog 1 (LRH-1) (which have been previously shown to be involved in activation of Rbp4 transcription), also responded to FSH stimulation. In addition, H-89, an inhibitor of protein kinase A (PKA), and the depletion of HMGA1, SF-1, and LRH-1 by small interfering RNAs (siRNAs), resulted in a dramatic loss of the induction of Rbp4 expression by FSH at both the mRNA and protein levels. These data indicate that the dynamic expression of Rbp4 is mainly regulated by FSH through the cAMP-PKA pathway, involving transcriptional factors HMGA1, SF-1, and LRH-1, in the mouse ovary during different stages of development and the estrous cycle.//////////////////
Ovarian localization
Granulosa, Theca
Comment
Brown JA et al 2003 reported the expression of retinol-binding protein and cellular retinol-binding protein in the bovine ovary.
Retinol (vitamin A) is essential for reproduction, and retinoids have been suggested to play a role in ovarian steroidogenesis, oocyte maturation, and early embryonic development. Retinol is transported systemically and intercellularly by retinol-binding protein (RBP). Within the cell, cellular retinol-binding protein (CRBP) functions in retinol accumulation and metabolism. Since the actions of retinoids are mediated, in part, by retinoid-binding proteins, the objective of this study was to investigate cell-specific expression of RBP and CRBP in the bovine ovary. Immunocytochemical analysis (ICC) localized RBP to the thecal and granulosa cell layers of antral and preantral follicles with the most intense staining in the cells of large, healthy follicles. The tunica adventitia of arterial blood vessels also exhibited RBP staining. Immunostaining of CRBP was most intense in the granulosa cells of preantral follicles and present, but diminished, in thecal and granulosa cells of antral follicles. Within the corpus luteum, both proteins were observed in large luteal cells, but only RBP was observed in small luteal cells. Northern blot analysis demonstrated that thecal and granulosa cells from antral follicles and luteal tissue expressed RBP and CRBP mRNA. Synthesis and secretion of RBP by thecal cells, granulosa cells, and luteal cells were demonstrated by immune-complex precipitation of radiolabeled RBP from the medium of cultured cells or explants, followed by SDS-PAGE and fluorography. Follicular fluid was collected from small (<5 mm) and large (8-14 mm) follicles, pooled according to follicular size, and analyzed for retinol, RBP, estradiol-17beta, and progesterone. Concentrations of retinol, RBP, and estradiol were greater in the fluid of large follicles. Results demonstrate retinoid-binding protein expression by bovine ovaries and provide physical evidence that supports the concept that retinoids play a role in ovarian function.
Follicle stages
Secondary, Antral
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: None fertility: fertile Comment: Association between retinol-binding protein 4 and polycystic ovary syndrome: A meta-analysis. Jia J 2014 et al.
Studies have examined the association between retinol-binding protein 4 (RBP4) and polycystic ovary syndrome (PCOS). However, the results have been inconsistent. To investigate the association between RBP4 and PCOS, we performed a meta-analysis. The Cochrane Library, MEDLINE, the ISI Web of Science, and EMBASE were searched to identify all of the studies that examined the relationship between circulating RBP4 levels and PCOS. Standard mean difference (SMD) values and 95% confidence interval (CI) were estimated and pooled using meta-analysis methodology. A total of seven studies were involved in the meta-analysis, which included a total of 636 subjects (260 controls and 376 patients with PCOS). The RBP4 level was higher in PCOS patients than in non-PCOS patients (random effects MD (95% CI)=0.69, [0.20, 1.18], P=0.006). However, the RBP4 level was not higher in nonobese PCOS patients than in nonobese controls (random effects MD (95% CI)=0.38, [-0.21, 0.98], P=0.20). The effect size revealed that the RBP4 level was higher in overweight or obese PCOS patients than weight-matched controls (fixed effects MD (95% CI)=7.95, [5.96, 9.93], P<0.05). In the subgroup analysis by region, the RBP4 level was higher in PCOS patients in Asia than controls (random effects MD (95% CI)=0.85, [0.54, 1.15], P<0.05), but not in European PCOS patients compared with controls (random effects MD (95% CI)=0.34, [-1.12, 1.80], P=0.65). This subgroup analysis also showed that nonobese PCOS patients have higher RBP4 levels than controls in Asia. Our meta-analysis results indicated that RBP4 might be a useful tool for identifying PCOS women.
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