scholarly journals Biological Functions of RBP4 and Its Relevance for Human Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Julia S. Steinhoff ◽  
Achim Lass ◽  
Michael Schupp
Keyword(s):  
Vitamin A ◽  
Membrane Receptors ◽  
Human Diseases ◽  
Retinol Binding Protein ◽  
Biological Functions ◽  
Retinol Binding Protein 4 ◽  
Retinoid Homeostasis ◽  
Hydrophobic Molecule ◽  
Retinyl Esters ◽  
Specific Membrane

Retinol binding protein 4 (RBP4) is a member of the lipocalin family 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 RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.

scholarly journals Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3987
Author(s):  
Nicasio Martin Ask ◽  
Matthias Leung ◽  
Rakesh Radhakrishnan ◽  
Glenn P. Lobo
Keyword(s):  
Cell Growth ◽  
Vitamin A ◽  
Visual Function ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Peripheral Tissues ◽  
Retinol Binding Protein 4 ◽  
Retinyl Esters ◽  
And Function

Vitamins are essential compounds obtained through diet that are necessary for normal development and function in an organism. One of the most important vitamins for human physiology is vitamin A, a group of retinoid compounds and carotenoids, which generally function as a mediator for cell growth, differentiation, immunity, and embryonic development, as well as serving as a key component in the phototransduction cycle in the vertebrate retina. For humans, vitamin A is obtained through the diet, where provitamin A carotenoids such as β-carotene from plants or preformed vitamin A such as retinyl esters from animal sources are absorbed into the body via the small intestine and converted into all-trans retinol within the intestinal enterocytes. Specifically, once absorbed, carotenoids are cleaved by carotenoid cleavage oxygenases (CCOs), such as Beta-carotene 15,15’-monooxygenase (BCO1), to produce all-trans retinal that subsequently gets converted into all-trans retinol. CRBP2 bound retinol is then converted into retinyl esters (REs) by the enzyme lecithin retinol acyltransferase (LRAT) in the endoplasmic reticulum, which is then packaged into chylomicrons and sent into the bloodstream for storage in hepatic stellate cells in the liver or for functional use in peripheral tissues such as the retina. All-trans retinol also travels through the bloodstream bound to retinol binding protein 4 (RBP4), where it enters cells with the assistance of the transmembrane transporters, stimulated by retinoic acid 6 (STRA6) in peripheral tissues or retinol binding protein 4 receptor 2 (RBPR2) in systemic tissues (e.g., in the retina and the liver, respectively). Much is known about the intake, metabolism, storage, and function of vitamin A compounds, especially with regard to its impact on eye development and visual function in the retinoid cycle. However, there is much to learn about the role of vitamin A as a transcription factor in development and cell growth, as well as how peripheral cells signal hepatocytes to secrete all-trans retinol into the blood for peripheral cell use. This article aims to review literature regarding the major known pathways of vitamin A intake from dietary sources into hepatocytes, vitamin A excretion by hepatocytes, as well as vitamin A usage within the retinoid cycle in the RPE and retina to provide insight on future directions of novel membrane transporters for vitamin A in retinal cell physiology and visual function.

Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

2015 ◽  
Vol 8 (4-6) ◽  
pp. 164-173 ◽  
Author(s):  
Katie Goodwin ◽  
Michal Abrahamowicz ◽  
Gabriel Leonard ◽  
Michel Perron ◽  
Louis Richer ◽  
...  
Keyword(s):  
Vitamin A ◽  
Binding Protein ◽  
Visceral Adiposity ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Retinol Binding Protein 4

scholarly journals Retinol-binding protein 4 (RBP4) and high sensitivity C-reactive protein (hs-CRP) levels in patients with diminished ovarian reserve (DOR): a cross-sectional study

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Wen Zou ◽  
Zehao Wang ◽  
Jing Xia ◽  
Jing Yang
Keyword(s):  
Oxidative Stress ◽  
Vitamin A ◽  
Ovarian Reserve ◽  
High Sensitivity ◽  
Diminished Ovarian Reserve ◽  
Retinol Binding Protein ◽  
C Reactive Protein ◽  
Retinol Binding Protein 4 ◽  
Reactive Protein ◽  
Hs Crp

Abstract Background Antioxidant/oxidant imbalance has been reported to be related to diminished ovarian reserve (DOR). Vitamin A (retinol), a kind of antioxidant, plays a role in restoring ovarian oxidative damage, while C-reactive protein (CRP) is the classical marker of oxidative stress and has recently been identified as an independent variable that is associated with low anti-Mullerian hormone (AMH) levels in young women with DOR. Additionally, retinol binding protein 4 (RBP4) can be considered a substitute for retinol in healthy, nonobese women. The study aim was to determine the relationship between serum RBP4, high sensitivity C-reactive protein (hs-CRP) concentrations and ovarian reserve in nonobese DOR patients. Methods This study included 24 DOR women and 48 normal ovarian reserve (NOR) women from the reproductive medical center of Renmin Hospital of Wuhan University. The serum RBP4 and high-sensitivity CRP (hs-CRP) levels were measured with ELISA kits. Results RBP4 levels (20,648.36 ± 5475.16 ng/ml vs 23,986.48 ± 5995.64 ng/ml, p = 0.025) were decreased, and hs-CRP levels (695.08 ± 1090.19 ng/ml vs 364.32 ± 786.29 ng/ml, p = 0.012) were increased in the DOR group. Serum RBP4 was positively related to AMH (Pearson r = 0.518, p = 0.000), while hs-CRP was negatively correlated with AMH (Spearman r = − 0.345, p = 0.005). after adjustments were made for the covariables, multiple line regression analysis showed that positive association between RBP4 and AMH still existed (β = 0.450, p < 0.001). Conclusion Decreased serum RBP4 levels and increased serum hs-CRP were observed in DOR patients in our study, and the strong correlation between RBP4 and AMH supports the notion that oxidative stress plays a role in DOR, and that appropriate levels of antioxidant vitamin A may be protective against ovarian reserve dysfunction.

Retinol binding protein 4 and its membrane receptors: a metabolic perspective

2015 ◽  
Vol 22 (1) ◽  
Author(s):  
Ronja Fedders ◽  
Matthias Muenzner ◽  
Michael Schupp
Keyword(s):  
Metabolic Diseases ◽  
Binding Protein ◽  
Current Data ◽  
Membrane Receptors ◽  
Retinol Binding Protein ◽  
Metabolic Effects ◽  
Retinol Binding Protein 4 ◽  
Underlying Mechanisms

AbstractNearly a decade of intense research has passed since the first report linking circulating retinol binding protein 4 (RBP4) to the development of insulin resistance. By now, a variety of underlying mechanisms have been identified; some of them are adherent to the canonical role of this circulating protein, which is to transport and deliver retinol to target tissues, and others that seem rather independent of retinol transport. Despite all these efforts, a consensus in the basic principles of RBP4’s metabolic effects has not been reached and some controversy remains. Using this as an opportunity, we here review and discuss current data on RBP4’s action on insulin sensitivity and its dependency on retinol homeostasis. We pay special attention to the involvement of RBP4 membrane receptors that were identified during these years, such as ‘stimulated by retinoic acid 6’ (STRA6), and whose identification added another layer of complexity to RBP4’s diverse actions. A better understanding of RBP4’s functions might allow its therapeutic exploitations, urgently needed in our period that is defined by an epidemic increase in metabolic diseases such as obesity and type 2 diabetes.

scholarly journals Retinol homeostasis in lambs given low and high intakes of vitamin A

1983 ◽  
Vol 50 (2) ◽  
pp. 235-248 ◽  
Author(s):  
Susan Donoghue ◽  
David S. Kronfeld ◽  
David Sklan
Keyword(s):  
Vitamin A ◽  
Plasma Clearance ◽  
Basal Diet ◽  
Retinol Binding Protein ◽  
Faecal Excretion ◽  
Several Variables ◽  
Supplemental Vitamin ◽  
Retinyl Esters ◽  
Plasma Retinol ◽  
Retinol Concentration

1. Four groups of lambs were fed on a low-carotene basal diet. One group received no supplemental vitamin A (mildly deficient). Remaining groups were supplemented daily with vitamin A acetate equivalent to 100 (control) 9000 (mildly intoxicated) and 18000 (severely intoxicated) μg retinol/kg body-weight. After 16 weeks lambs received a bolus of[15−3H]retinol intravenously; blood, urine and faeces were sampled for 48 h.2. Plasma retinol was complexed to a protein of 20000 molecular weight (MW), which in turn was complexed to a protein of 65000 MW; these proteins correspond respectively to retinol-binding protein and prealbumin. Plasma retinol concentration reached plateau values in intoxicated lambs, but plasma retinyl ester concentrations increased rapidly when liver contents of both retinol and retinyl esters exceeded approximately 10 and 100 mg respectively and kidney contents of both retinol and retinyl esters exceeded 30 μg. Labelled compounds, more polar than retinol, were found in plasma; their concentration increased tenfold in intoxicated lambs within 48 h.3. Plasma retinol transport rates were 0·1, 10·5 and 11·8 times control values, and clearance rates were 0·3, 14·1 and 14·3 times control values in mildly-deficient, and mildly- or severely-intoxicated lambs respectively. Turnover of retinol increased rapidly when liver contents of retinol and retinyl esters exceeded approximately 10 and 100 mg respectively and kidney contents of both retinol and retinyl esters exceeded approximately 30 μg. Plasma clearance of retinyl esters was unchanged with intake. Faecal excretion of tracer increased linearly with plasma retinol clearance.4. Our findings identify, several variables that appear to be involved in retinol homeostasis, including plasma retinol clearance and excretion.

scholarly journals Retinol, Retinoic Acid, and Retinol-Binding Protein 4 are Differentially Associated with Cardiovascular Disease, Type 2 Diabetes, and Obesity: An Overview of Human Studies

2019 ◽  
Vol 11 (3) ◽  
pp. 644-666 ◽  
Author(s):  
Thomas Olsen ◽  
Rune Blomhoff
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Binding Protein ◽  
Human Studies ◽  
Retinol Binding Protein ◽  
Retinol Binding Protein 4 ◽  
Vitamin A Metabolism

ABSTRACT Vitamin A is a fat-soluble essential nutrient obtained from plant- and animal-based sources that has roles in growth, vision, and metabolism. Vitamin A circulates mainly as retinol bound to retinol-binding protein 4 (RBP4), and is delivered to tissues and converted to retinoic acid, which is a ligand for several nuclear receptors. In recent years, aspects of vitamin A metabolism have been under scrutiny with regards to the development of metabolic and lifestyle diseases including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and overweight and obesity in humans. Studies have mainly focused on RBP4 in this context, whereas the major circulating form, retinol, and the major bioactive form, retinoic acid, have been overlooked in this regard until recently. As one of the main roles of RBP4 is to deliver retinol to tissues for biological action, the associations of retinol and retinoic acid with these diseases must also be considered. In this review, we summarize and discuss recent and available evidence from human studies with focus on retinol, retinoic acid, and RBP4 and provide an overview of these crucial components of vitamin A metabolism in CVD, T2DM, and obesity. In summary, retinol was found to be both inversely and positively associated with CVD whereas the associations with T2DM and obesity were less clear. Although only a few studies have been published on retinoic acid, it was inversely associated with CVD. In contrast, serum RBP4 was mostly found to be positively associated with CVD, T2DM, and obesity. At present, it is difficult to ascertain why the reported associations differ depending on the compound under study, but there is a clear imbalance in the literature in disfavor of retinol and retinoic acid, which needs to be considered in future human studies.

scholarly journals Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation

2004 ◽  
Vol 383 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Andrei MOLOTKOV ◽  
Norbert B. GHYSELINCK ◽  
Pierre CHAMBON ◽  
Gregg DUESTER
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Alcohol Dehydrogenase ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Gene Encoding ◽  
Retinyl Ester ◽  
Ester Formation ◽  
Retinyl Esters ◽  
Cellular Retinol Binding Protein

Vitamin A homoeostasis requires the gene encoding cellular retinol-binding protein-1 (Crbp1) which stimulates conversion of retinol into retinyl esters that serve as a storage form of vitamin A. The gene encoding alcohol dehydrogenase-1 (Adh1) greatly facilitates degradative metabolism of excess retinol into retinoic acid to protect against toxic effects of high dietary vitamin A. Crbp1−/−/Adh1−/− double mutant mice were generated to explore whether the stimulatory effect of CRBP1 on retinyl ester formation is due to limitation of retinol oxidation by ADH1, and whether ADH1 limits retinyl ester formation by opposing CRBP1. Compared with wild-type mice, liver retinyl ester levels were greatly reduced in Crbp1−/− mice, but Adh1−/− mice exhibited a significant increase in liver retinyl esters. Importantly, relatively normal liver retinyl ester levels were restored in Crbp1−/−/Adh1−/− mice. During vitamin A deficiency, the additional loss of Adh1 completely prevented the excessive loss of liver retinyl esters observed in Crbp1−/− mice for the first 5 weeks of deficiency and greatly minimized this loss for up to 13 weeks. Crbp1−/− mice also exhibited increased metabolism of a dose of retinol into retinoic acid, and this increased metabolism was not observed in Crbp1−/−/Adh1−/− mice. Our findings suggest that opposing actions of CRBP1 and ADH1 enable a large fraction of liver retinol to remain esterified due to CRBP1 action, while continuously allowing some retinol to be oxidized to retinoic acid by ADH1 for degradative retinoid turnover under any dietary vitamin A conditions.

Sign in / Sign up

Export Citation Format

Share Document