Retinol Binding Protein 4 In Patients Research Articles

Assessment of Circulating Retinol Binding Protein-4 Levels in Patients with Compound Heterozygosity for Hb S and β-Thalassemia

Background: Retinol Binding Protein-4 (RBP-4) is a member of the lipocalin family of proteins and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP-4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP-4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. While, after its dissociation from TTR and retinol release, retinol-free apo-RBP4 in the circulation is filtrated by the kidney. More than 99% of that is reabsorbed by the proximal renal tubule, which renders urinary RBP-4 a highly sensitive marker for tubular dysfunction. We and other have shown previously that the patients with Sickle Cell Disease (SCD) have deficiencies or suboptimal levels of vitamin A, while recently (Br J Haematol. 2023;doi:10.1111/bjh.18862) higher urine RBP-4 in patients with SCD especially in those with persistent albuminuria but without an association of urine RBP-4 levels with estimated glomerular filtration rate (eGFR). In this context, we aimed to investigate the potential clinical significance of circulating plasma RBP-4 levels and its association with disease features in Caucasian patients with compound heterozygosity for HbS and β-thalassemia (HbS/β thal). Patients and Methods: Ninety Caucasian adult patients with HbS/β thal at steady phase were included in the study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients was diabetic and has received any transfusions at least 6-monthes before enrollment in the study. RBP-4 concentration was measured with an immunoturbidimetric assay applied in an automated chemistry analyzer, along with hematologic, and series of blood chemistry parameters reflecting renal, cardiac and endothelial dysfunction. eGFR values were calculated using the CKD-EPI (Cystatin C and/or Creatinine equations). Results: We found that: a) Plasma RBP-4 levels were significantly lower in patients with HbS/β thal compared to controls, 30.5±2.7mg/L (Confidence Intervals (CI): 28.8;32.2mg/mL) vs 36.3±3.6mg/L (CI: 32.7;39.9mg/mL), p<0.003. The patients with β + genotypehave higher RBP-4 levels than those with β 0 genotype (p<0.05), whereas patients treated with hydroxycarbamide(50/90) are more likely to express higher RBP-4 levels, p-trend=0.06; b) RBP-4 levels in patients with HbS/β thal correlated positively with their age, body mass index (BMI) and Hb levels (r=0.264, p=0.012; r=0.334, p=0.001 and r=0.209, p<0.05, respectively; c) RBP-4 levels in patients with HbS/β thal correlated with total bilirubin, total cholesterol, triglycerides and uric acid (r=-0.452, p<0.001; r=0.395, p=0.004; r=0.292, p=0.015 and r=0.435, p<0.001, respectively); d) RBP-4 levels in patients with HbS/β thal correlated negatively with eGFR values rho=-0.360, p=0.003 and hs-CRP concentrations r=-0.309, p=0.004 and e) No correlations were found between RBP-4 levels with markers of cardiac and endothelial dysfunction such as High Sensitivity Troponin T, Growth Differentiation Factor-15, von Willebrand factor antigen, Α Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif 13 antigen and P-Selectin, as well as with number of vaso-occlusive crisis and mean pulmonary arterial pressure in the patients. Conclusions: These findings demonstrate a multifactorial role of RBP-4 in patients with HbS/β thal as the circulating levels of the protein correlate significantly with markers of erythropoiesis, inflammation and renal function. It is unclear of this study if RBP-4 has any specific functions in patients with HbS/β thal. However, RBP-4 should be more investigated in order to determine its clinical significance and in the case of sickle cell nephropathy both plasma and urine measurements should be considered.

Study of decreased serum levels of retinol binding protein 4 in major depressive disorder

BackgroundStudies in western populations find that obesity and depression are positively correlated. Adipokines secreted by adipose tissue may serve as the crosstalk link between peripheral tissue and central nervous system, which mediates the relationship between obesity and depression. ObjectiveThis study aimed to investigate serum retinol-binding protein 4 (RBP4) concentration in patients with major depressive depression (MDD) and clarify its possible association with depression. MethodsMajor depressive disorder patients (n = 237), healthy controls (n = 48) were collected from June 2017 to October 2019. The measurement of RBP4 levels was performed by Advia 2400 automatic biochemistry analyzer. Depressive symptoms of patients were assessed using the 24-item Hamilton Depression Scale (HAMD-24). Results(1) Serum RBP4 levels of MDD patients were significantly lower than that of the control group [(34.25 ± 8.82) mg/L vs (37.56 ± 8.83) mg/L] (P < 0.05) which was independent from obesity; (2) The level of RBP4 [(31.13 ± 9.16) mg/L] in suicide attempt (SA) group was significantly lower than that in the control group and non-suicide attempt (non-SA) group [(35.55 ± 8.37)mg/L](P < 0.05); (3) There was no significant correlation between serum RBP4 concentration and HAMD-24 score (P > 0.05); serum RBP4 concentrations were positively associated with age, age of onset and duration of disease (r = 0.325, 0.298, 0.135; P < 0.001, P < 0.001, P = 0.038) in depressive patients. (4) The level of serum RBP4 was positively correlated with TC, TG, and LDL-C (r = 0.350, 0.207, 0.268; P < 0.001, P = 0.001, P < 0.001), but not with other blood lipid indexes. ROC curve of RBP4 for MDD revealed an area under the curve of 0.603 and a sensitivity of 81.3%, specificity of 80%. ConclusionThe level of RBP4 in patients with MDD was lower than that in the normal control group, which might be related to the prognosis of patients with depression.

Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients

ObjectiveRetinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA.Materials and methodsCartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing.ResultsThe OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin.ConclusionsWe show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.

Serum retinol-binding protein 4 and the risk of ischemic stroke in Egyptian patients with hypothyroidism

ObjectiveIschemic stroke (IS) is one of the major causes of disability and death worldwide. Effective prevention remains the best approach to reduce the burden of stroke. Adipokines can serve as a key messenger to central energy homeostasis and metabolic homeostasis. Retinol-binding protein 4 (RBP4), a retinol transporter, is elevated in insulin resistance. Controversy exists regarding the role of RBP4 in thyroid diseases. The objective of this study was to evaluate serum RBP4 in patients with hypothyroidism and to assess the association of serum RBP4 with susceptibility of IS.Patients and methodsThis case–control study included 50 healthy individuals as a control group and 90 patients with hypothyroidism, who were stratified into two subgroups: patients with IS and patients without IS. All participants were subjected to history taking and clinical, laboratory, and radiological evaluation.ResultsSerum RBP4 levels were significantly higher in hypothyroid patient, especially patients with IS, compared with the nonstroke group. Interestingly, serum RBP4 level was positively correlated with vascular and metabolic risk factors. Moreover, diastolic and systolic blood pressures, triglyceride, free T3, as well as thyroid-stimulating hormone, were independently correlated with serum RBP4 by linear regression analysis test. The diagnostic power of serum RBP4 level in differentiating hypothyroidism from controls was revealed at the cutoff value of 12.25, with area under the curve of 0.909 (95% confidence interval: 0.861–0.957). However, the diagnostic power of serum RBP4 level in differentiating hypothyroid patient with IS from those without stroke was revealed at the cutoff values of 11.4, with area under the curve of 0.822 (95% confidence interval: 0.737–0.906). In conclusion, the higher levels of serum RBP4 in hypothyroidism, especially in patients with IS, were associated with metabolic and glucose abnormalities, and thus, it could be used as a promising predictive biomarker of IS in hypothyroidism.

Research on the changes and significance of serum RBP4 level in patients with senior coronary heart disease accompanying diabetes mellitus

Objective: To explore the significance of serum Retinol binding protein 4 (RBP4) and its relationship with coronary artery lesion in patients with senior coronary heart disease accompanying T2DM by determining the level of serum RBP4 and Gensini score.Methods: 30 cases of patients who were 60 years old above with coronary heart disease accompanying T2DM were selected and included in the experimental group, and 30 cases of patients of 60 years old above with coronary heart disease alone were included in the control group. Both groups of patients were given CAG examinations. In addition, Gensini score was calculated according to different degrees and parts of coronary artery lesion. It was required to record each patient’s age, gender, fasting blood glucose (FPG), triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), glycated hemoglobin (HbA1c) and other laboratory examination indexes. ELISA was used to detect the level of serum RBP4 in each group, and statistical analysis was performed to the data in each group.Results: (1) RBP4 level, GS score, FPG and LDL-C in the experimental group were all higher than those in the control group, and the difference was of statistical significance (p &lt; .05). There was no statistically significant difference in age, gender, TC, TG and HDL-C between two groups. (2) RBP4 was positively correlated to FPG and HbA1c. (3) In patients with senior coronary heart disease accompanying diabetes mellitus, HbA1c was positively correlated to GS score, RBP4 and FPG. (4) RBP4 was a risk factor for coronary artery stenosis in patients with senior coronary heart disease accompanying diabetes mellitus.Conclusions: The level of serum RBP4 in patients with senior coronary heart disease accompanying diabetes mellitus is higher than that in patients with coronary heart disease alone, with a deeper degree of coronary artery lesion. The level of serum RBP4 is increased with the degree of lesion deepened in patients with senior coronary heart disease, suggesting that the level of serum RBP4 is expected to be an early predictor of coronary artery lesion for patients with senior coronary heart disease.

Assessment of serum Retinol-Binding Protein-4 Levels in patients with acute exacerbation of chronic obstructive disease at intensive care unit

BackgroundChronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity. Retinol-Binding Protein 4 (RBP4), has been recognized as an adipokine implicated in COPD. In this study we assessed the level of serum RBP4 in patients with acute exacerbation of COPD (AECOPD) at intensive care unit and compared to stable patients and healthy controls. ObjectiveAssessment of serum RBP4 in patients with AECOPD at intensive care unit and the possibility of its use as a predictive biomarker for mortality in AECOPD. Patients and methodThis study was conducted on Ninety persons divided into 3 groups: Group 1: Forty patients with AECOPD admitted to ICU. Group 2: Thirty patients with stable COPD. (Group 1 and 2 were classified according to Global Initiative for COPD (GOLD, 2015). Group 3: Twenty healthy persons as a control. They were subjected to full history taking, clinical examination, Investigations as liver and kidney functions and serum RBP4 assessment by Enzyme-linked immunosorbent assays.Samples were collected within first 24 h of admission. ResultsThere was a significant decrease in serum RBP4 in patients with AECOPD (mean 71.73 ± 33.43) mg/L admitted in ICU than other 2 groups: stable COPD (mean 177.53 ± 93.24) mg/L and healthy controls (mean 231.21 ± 122.90) mg/L and further decrease in non survivors (mean 48.57 ± 16.26) mg/L than survivors (mean 106.46 ± 18.85) mg/L. (Z = 5.301, p ≤ .001). RBP4 was positively correlated with body mass index and serum albumin, while negatively correlated with serum creatinine, c reactive protein, total bilirubin and APACHE-II score. ConclusionSerum-Retinol-Binding Protein-4 can be used as a predictive biomarker for mortality in AECOPD. We recommend that the serum RBP4 should be taken in consideration as a part of the assessment of mortality of AECOPD patients admitted in ICU.

Factors associated with survival after pancreatic cancer surgical resection

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Hepatic modification of pancreatic exosomes in experimental acute pancreatitis

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Role of faecal elastase in predicting echoendoscopic findings in chronic pancreatitis

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Zeb1 in stromal myofibroblasts fosters Kras-driven pancreatic cancer development

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Metachronous liver metastasis seven years after a whipple procedure for ductal adenocarcinoma of the pancreas

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Evaluation of insulin-like growth factor (IGF-1) and retinol binding protein (RBP-4) levels in patients with newly diagnosed pancreatic adenocarcinoma (PDAC)

Background/ObjectivesThe elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP). MethodsThe study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz. ResultsIn PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other. ConclusionsDiabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Significance of RBP4 in patients with gestational diabetes mellitus: a case-control study of Han Chinese women

The role of retinol binding protein 4 (RBP4) in insulin resistance was recently identified. Our study investigated the correlation between RBP4 levels with lipid and glucose metabolism in a case-control study of women with gestational diabetes mellitus (GDM). Between May 2008 and May 2010, 70 pregnant women (24–28 weeks gestation) were recruited, including 35 women with GDM and 35 healthy controls. Blood samples were collected prior to and after oral glucose tolerance tests (OGTT) to detect serum RBP4, insulin, glycated hemoglobin, triglyceride (TG) and total cholesterol (TC) levels; the insulin resistance index (HOMA-IR) was calculated. Serum RBP4 levels in the GDM group were significantly higher than the control group (22.9 ± 3.09 µg/ml versus 17.9 ± 3.91 µg/ml; p < 0.01). Insulin, TC and TG levels in the GDM group and the control group were all significantly higher than the control group (p < 0.05). Serum RBP4 levels in the GDM group were correlated with HOMA-IR, TG and blood glucose levels at 1 h and 2 h after glucose was administered (r = 0.49, 0.49, 0.52,0.52, respectively; p < 0.01). In conclusion, serum RBP4 levels are elevated in GDM cases than controls. In addition, RBP4 correlates with abnormalities of insulin resistance, glucose and lipid metabolism.

Association of a Novel Adipokine with Insulin Resistance and Disease Severity in HCV Infected Patients

Retinol-binding protein 4 (RBP4) has been identified as a protein contributing to insulin resistance (IR). As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic hepatitis C virus infected patients (CHC). This study aimed to evaluate the role of serum retinol binding protein 4 (RBP-4) as a predictor for early detection of insulin resistance (IR) in patients with CHC infection. Research Design and Methods: Serum RBP4 was measured in 60 non diabetic CHC Patients classified according to Child- Pugh classification (Child A, Child B, Child C), 20 diabetic CHC patients and 20 age- and sex-matched healthy blood donors served as control subjects. RBP-4 correlation with the homeostasis model assessment of insulin resistance index (HOMA-IR) and metabolic factors was investigated. Results: Serum RBP-4 levels were significantly lower in HCV infected patients and HCV diabetic patients compared with controls (HCV 16545.17± 10633.16, Diabetic HCV 10310 ± 4371.31, Control 27820.0 ± 9316.46, P< 0.001). In addition, serum levels of RBP-4 significantly decreased between all stages of cirrhosis, with the lowest level in Child C. HOMA-IR not significantly higher in HCV infected patients compared to control (HCV 5.54 ± 3.67, and Control 4.11 ± 2.42). RBP-4 levels correlate positively with GGT (P<0.01), CHOL (P<0.05) and TG (P<0.05) in HCV Child C, additionally, it shows significant positive correlation with TG (P< 0.05) in HCV Child B. Conclusions: Disease severity may limit the role of RBP4 as a predictor of IR in CHC. These data demonstrate that RBP4 in CHC patients decreased due to reduced hepatic production, and it is not associated with insulin resistance. Keywords: HCV, RBP4, Insulin Resistance Abbreviations: RBP4: Retinol-binding protein 4, IR: insulin resistance, HOMA-IR: homeostasis model assessment of insulin resistance index, CHC: Chronic Hepatitis C Virus.

Retinol-Binding Protein 4 Induces Inflammation in Human Endothelial Cells by an NADPH Oxidase- and Nuclear Factor Kappa B-Dependent and Retinol-Independent Mechanism

Serum retinol-binding protein 4 (RBP4) is the sole specific vitamin A (retinol) transporter in blood. Elevation of serum RBP4 in patients has been linked to cardiovascular disease and diabetic retinopathy. However, the significance of RBP4 elevation in the pathogenesis of these vascular diseases is unknown. Here we show that RBP4 induces inflammation in primary human retinal capillary endothelial cells (HRCEC) and human umbilical vein endothelial cells (HUVEC) by stimulating expression of proinflammatory molecules involved in leukocyte recruitment and adherence to endothelium, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). We demonstrate that these novel effects of RBP4 are independent of retinol and the RBP4 membrane receptor STRA6 and occur in part via activation of NADPH oxidase and NF-κB. Importantly, retinol-free RBP4 (apo-RBP4) was as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory molecules in both HRCEC and HUVEC. These studies reveal that RBP4 elevation can directly contribute to endothelial inflammation and therefore may play a causative role in the development or progression of vascular inflammation during cardiovascular disease and microvascular complications of diabetes.

Plasma level of RBP4 in patients with coronary heart disease and the effect of hyperinsulinemia

To evaluate the change of plasma level of retinol binding protein 4 (RBP4) in patients with coronary heart disease, and to explore the effect of hyperinsulinemia. This study was carried out at Xiangya Hospital of Central South University, China, from September 2009 to May 2010. Thirty patients with coronary artery disease (the CAD group) were confirmed by coronary angiography, 29 patients with CAD plus hyperinsulinemia (the CAD+HIns group), and 30 healthy subjects were enrolled as controls (the control group). The peripheral blood sample from the anticubital vein was collected aseptically in all the subjects to measure the RBP4 by enzyme linked immunosorbent-assay (ELISA). The height, weight, body mass index (BMI) the waist-to-hip ratio (WHR), the blood pressure, the fasting plasma glucose (FPG), the fasting insulin (Fins), the 2-hour postprandial inslulin (2hPIns), and the homeostasis model assessment-insulin resistance index (HOMA-IR) was measured. The lipids, high sensitivity C reactive protein (hsCRP), uric acid(UA), free fatty acids (FFA) were all examined. The level of plasma RBP4 in the CAD+HIns group was higher than that in the CAD group and the control group (both P<0.01), with no significant difference of plasma RBP4 between the CAD group and the control group (P>0.05). Correlation analysis showed that the plasma RBP4 level was significantly correlated with BMI, FPG, FIns, 2hPIns, HOMA-IR, TG, HDL-C, UA, and hsCRP (r=0.259, 0.331, 0.582, 0.452, 0.600, 0.236, -0.290, 0.243, 0.231, respectively; all P>0.05). Multiple regression analysis showed that BMI, 2hPIns, and HOMA-IR were the independent factors related to RBP4. The plasma level of RBP4 does not increase in the CAD group, but it is high in the CAD +HIns group. RBP4 level is related to BMI, lipids, UA, and other cardiovascular risk factors. BMI, 2hPIns, and HOMA-IR are the independent factors associated with RBP4.

Increased Levels of Retinol Binding Protein 4 in Patients With Advanced Heart Failure Correct After Hemodynamic Improvement Through Ventricular Assist Device Placement

Chronic heart failure is associated with higher risk for developing diabetes mellitus. Secretory products from adipocytes may contribute to the deterioration in glycemic control and increased insulin resistance (IR). Retinol binding protein 4 (RBP4) is an adipose tissue-derived protein with pro-diabetogenic effects. The aim of the present study was to investigate the relationship of RBP4 in patients with heart failure. Serum levels of RBP4, insulin, and fasting glucose were assessed in 58 patients with severe heart failure at the time of left ventricular assist device (LVAD) implantation and in 44 patients at the time of explantation, as well as in 10 normal control subjects. Serum RBP4 levels were measured by specific enzyme-linked immunosorbent assay, and IR was assessed using the homeostatic model of IR (HOMA-IR). Fasting glucose, insulin and HOMA-IR were significantly higher in patients at the time of LVAD implantation compared to controls (all P<0.01). RBP-4 and HOMA-IR significantly decreased after LVAD implantation (21.7 ± 8.8 mg/dl to 16.0 ± 3.8 mg/dl, P<0.05; 4.2 ± 2.7 to 2.5 ± 2.0, P<0.01). Patients with advanced heart failure have increased levels of RBP4, and LVAD implantation reduces RBP4. These findings implicate RBP4 in the cascade of reversible metabolic derangements in advanced heart failure.

Serum Retinol-Binding Protein 4 Levels in Patients with Diabetic Retinopathy

Retinol-binding protein 4 (RBP4) has been reported to be involved in the development of insulin resistance and diabetes. This study was designed to investigate serum levels of RBP4 in patients with type 2 diabetes with and without diabetic retinopathy. Based on ophthalmological examination, 92 patients with type 2 diabetes were divided into three subgroups: those without diabetic retinopathy (NDR; n = 40); those with simple diabetic retinopathy (SDR; n = 37); and those with proliferative diabetic retinopathy (PDR; n = 15). The serum RBP4 level was significantly elevated in individuals with PDR compared with those with NDR or SDR. There was a significant positive correlation between serum RBP4 level and the urine albumin excretion rate (r = 0.219). This study showed that RBP4 may be involved in the process of diabetic retinopathy and may be a novel biomarker for its diagnosis and treatment in diabetic patients.

Retinol binding protein 4 – a novel association with early-onset preeclampsia

Dysregulation of maternal circulating adipokines has been implicated in several "great obstetrical syndromes" including preeclampsia (PE), small-for-gestational age (SGA) neonate and fetal death (FD). It has been suggested that adipokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. Retinol binding protein 4 (RBP4), a novel adipokine, plays a role in obesity-related disorders, as well as in the regulation of the immune response. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in patients with PE and in those with an SGA neonate or FD. This cross-sectional study included patients in the following groups: 1) normal pregnancy (n=134); 2) PE (n=104); 3) SGA neonate (n=28); and 4) FD (n=37). Maternal plasma RBP4 concentrations were determined by ELISA. Non-parametric statistics were used for analysis. 1) The median maternal plasma RBP4 concentration was higher among patients with PE than in those with a normal pregnancy (P=0.03); 2) The median maternal plasma RBP4 concentrations of patients with preterm PE (<37 weeks) was higher than that of those with term PE (P=0.017) and than that of those with a normal pregnancy (P=0.002); 3) The median maternal plasma RBP4 concentration did not differ significantly between patients with a normal pregnancy and those with an SGA neonate or with an FD; 4) Among normal pregnant women, the maternal plasma RBP4 concentrations did not correlate with pre-pregnancy body mass index, gestational age at blood sampling and neonatal birthweight. 1) Preeclampsia, but not pregnancy with an SGA neonate or an FD, is associated with a higher median maternal plasma concentration of RBP4 than normal pregnancy; 2) Preterm PE, and specifically early-onset PE, is associated with higher median RBP4 concentrations in maternal plasma compared to term PE. These findings suggest a role for RBP4 in the pathogenesis of preterm PE, but not in SGA and FD.

Insulin Resistance in Liver Cirrhosis Is Not Associated With Circulating Retinol-Binding Protein 4

Retinol-binding protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and elevated serum RBP4 indicates overt or impending insulin resistance in lean, obese, and type 2 diabetic subjects. As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic liver disease (CLD). Serum RBP4 was measured in 111 CLD patients. Ninety-nine age- and sex-matched healthy blood donors served as control subjects. RBP4 gene expression was also quantified in normal and cirrhotic rat liver. In CLD patients, serum RBP4 was significantly reduced compared with healthy control subjects and closely correlated with the stage of liver cirrhosis. CLD patients without cirrhosis showed normal RBP4 concentrations, which correlated with serum glucose and insulin secretion and inversely correlated with insulin sensitivity. In patients with Child A-C liver cirrhosis, however, RBP4 was not correlated with glucose metabolism or other adipokines, such as adiponectin or resistin, but closely linked to the hepatic biosynthetic capacity, fibrotic changes in liver histology, or clinical complications such as portal hypertension. In an animal model of experimental cirrhosis, hepatic RBP4 gene expression decreased in cirrhotic liver. RBP4 appears, unlike in obesity or type 2 diabetes, not to be a relevant systemic factor in the pathogenesis of insulin resistance in liver cirrhosis. Liver function has a tremendous impact on RBP4 levels, and future studies will need to take liver function into account when examining serum RBP4 levels.