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 A Functional Binding Domain in the Rbpr2 Receptor is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish

2020 ◽  
Author(s):  
Ashish K. Solanki ◽  
Altaf A Kondkar ◽  
Joseph Fogerty ◽  
Yanhui Su ◽  
Seok-hyung Kim ◽  
...  
Keyword(s):  
Vitamin A ◽  
Cell Survival ◽  
Photoreceptor Cell ◽  
Binding Protein ◽  
Binding Domain ◽  
Human Vision ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Binding Residues ◽  
Vitamin A Transport

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is however not expressed in systemic tissues, where there is high-affinity RBP4 binding and ROL uptake. We tested the hypothesis, that the second retinol-binding protein 4 receptor 2 (Rbpr2) which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, that were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatments rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

scholarly journals A Functional Binding Domain in the Rbpr2 Receptor Is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1099
Author(s):  
Ashish K. Solanki ◽  
Altaf A. Kondkar ◽  
Joseph Fogerty ◽  
Yanhui Su ◽  
Seok-Hyung Kim ◽  
...  
Keyword(s):  
Vitamin A ◽  
Cell Survival ◽  
Photoreceptor Cell ◽  
Binding Protein ◽  
Binding Domain ◽  
Human Vision ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Binding Residues ◽  
Vitamin A Transport

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is, however, not expressed in systemic tissues, where there is high affinity RBP4 binding and ROL uptake. We tested the hypothesis that the second retinol binding protein 4 receptor 2 (Rbpr2), which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR-generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, which were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatment rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

scholarly journals Influence of Supplemental, Dietary Vitamin A on Retinol-Binding Protein Concentrations in the Plasma of Preruminant Calves

2001 ◽  
Vol 84 (3) ◽  
pp. 641-648 ◽  
Author(s):  
B.J. Nonnecke ◽  
M.P. Roberts ◽  
J.D. Godkin ◽  
R.L. Horst ◽  
D.C. Hammell ◽  
...  
Keyword(s):  
Vitamin A ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Dietary Vitamin

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 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.

scholarly journals Serum and intracellular retinol transport in the equine

1982 ◽  
Vol 47 (2) ◽  
pp. 273-280 ◽  
Author(s):  
D. Sklan ◽  
Susan Donoghue
Keyword(s):  
Vitamin A ◽  
Gel Filtration ◽  
Protein Aggregates ◽  
Retinyl Palmitate ◽  
Hydrolase Activity ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Protein Aggregate ◽  
Retinyl Esters ◽  
Four Levels

1. Serum and intracellular distribution of retinol was determined in equines maintained on four levels of vitamin A intake.2. The form of retinol transported in serum was determined by gel filtration and chromatography to be a complex of retinol bound to a protein of molecular weight (MW) of approximately 20000, which was in turn complexed probably with prealbumin to yield a complex with a MW of 75000 to 80000.3. Increasing dietary vitamin A levels enhanced the concentration of lipoprotein-bound retinyl esters in the plasma.4. Vitamin A in the liver cytosol was found predominantly as retinyl esters in a lipid–protein aggregate of MW approximately 2 × 106 and hydrated density of 1·063–1·111. In the kidney and adrenal gland, two Iipid–protein entitites were found with MW of approximately 1·8 × 106 and 1·7 × 105 respectively. These fractions contained approximately 40 and 20% lipid respectively and had densities of 1·063–1·111 and approximately 1·21.5. All lipid–protein aggregates were associated with retinyl palmitate hydrolase activity and guanidine treatment released a 15000 MW material, presumably intracellular retinol-binding protein.6. Increasing dietary vitamin A enhanced the proportion of retinol in the 1·7 × 105 fraction.7. Findings in equine plasma and liver resemble previous observations in other species. The characterization of two new lipid–protein aggregates in equine kidney and adrenal glands, which have hydrolase activity, may be important in intracellular retinol transport and metabolism, especially in animals subjected to high intakes of vitamin A.

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