Plasma retinol binding protein: structure and function of the prototypic lipocalin

Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.

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“…It transports retinol from the liver to the peripheral tissues (21). Plasma RBP4 levels positively correlate with retinol levels (22).…”

Section: Characteristics Of Rbp4mentioning

confidence: 99%

RBP4: a controversial adipokine

Kotnik

Fischer‐Posovszky

Wabitsch

2011

European Journal of Endocrinology

210

165

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“…2 is the principal carrier of vitamin A in the blood (1)(2)(3)(4). It was first proposed in the 1970s that there exists a cell surface receptor that mediates vitamin A uptake from RBP on the retinal pigment epithelium and small intestine cells (5)(6)(7)(8)(9)(10).…”

Section: Plasma Retinol-binding Protein (Rbp)mentioning

confidence: 99%

An Essential Ligand-binding Domain in the Membrane Receptor for Retinol-binding Protein Revealed by Large-scale Mutagenesis and a Human Polymorphism

Kawaguchi

Wiita

et al. 2008

Journal of Biological Chemistry

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Plasma retinol-binding protein (RBP), the principal carrier of vitamin A in the blood, delivers vitamin A from liver, the site of storage, to distant organs that need vitamin A, such as the eye, brain, placenta, and testis. STRA6 is a high-affinity membrane receptor for RBP and mediates vitamin A uptake in these target organs. STRA6 is a 74-kDa multi-transmembrane domain protein that represents a new class of membrane transport protein.In this study, we used an unbiased strategy by analyzing >900 random mutants of STRA6 to study its structure and function, and we identified an essential RBP-binding domain in STRA6. Mutations in any of the three essential residues in this domain can almost completely abolish binding of STRA6 to RBP and its vitamin A uptake activity from holo-RBP without affecting its cell surface expression. We have also functionally characterized the mutations in human STRA6 that cause severe birth defects as well as several human polymorphisms. All STRA6 mutants associated with severe birth defects have largely abolished vitamin A uptake activity, consistent with the severe clinical phenotypes. In addition, we have identified a human polymorphism that significantly reduces the vitamin A uptake activity of STRA6. Interestingly, the residue affected by this polymorphism is located in the RBP-binding domain we identified, and the polymorphism causes decreased vitamin A uptake by reducing RBP binding. This study identifies an essential functional domain in STRA6 and a human polymorphism in this domain that leads to reduced vitamin A uptake activity. Plasma retinol-binding protein (RBP)2 is the principal carrier of vitamin A in the blood (1-4). It was first proposed in the 1970s that there exists a cell surface receptor that mediates vitamin A uptake from RBP on the retinal pigment epithelium and small intestine cells (5-10). During the past 3 decades, there has been mounting evidence for the existence of RBP receptors on diverse types of tissues, including the placenta (11-13), choroid plexus (12, 14), Sertoli cells and peritubular cells of the testis (12,(15)(16)(17)(18), macrophages (19), and skin (12,20). There are also indirect pieces of evidence for the existence of an RBP receptor. For example, in an unbiased search for a serum factor that stimulates the growth of B cells, it was found that the vitamin A-RBP complex (holo-RBP) is this factor (21). Using an unbiased strategy combining photo-cross-linking, high-affinity purification, and mass spectrometry, the RBP receptor was identified as STRA6, a multi-transmembrane protein of previously unknown function (22). STRA6 binds to RBP with high affinity and specificity and facilitates the transport of vitamin A into the cell. STRA6 was originally identified as a retinoic acid-stimulated gene in cancer cell lines (23, 24).STRA6 has not been systematically characterized at the structural and functional level and is not homologous to any protein with known function. In this study, we used two complementary approaches to study the structure and functi...

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“…The interior of the barrel forms a binding site for small hydrophobic ligands and this structural property is the basis for a surprisingly wide array of biological functions. Retinol-binding protein and prostaglandin D-synthase from mammals, insect bilin-binding protein and plant violaxanthinde-epoxygenase are examples of lipocalins [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Redox properties of the lipocalin α1-microglobulin: Reduction of cytochrome c, hemoglobin, and free iron

Maria

Klapyta

Åkerström

2005

Free Radical Biology and Medicine

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Abstractα 1 -microglobulin (α 1 m) is a 26 kDa plasma and tissue glycoprotein. The protein has a heterogeneous yellow-brown chromophore consisting of small unidentified prosthetic groups localized to a free thiol group (C34) and three lysyl residues (K92, K118 and K130) around the entrance to a hydrophobic pocket. It was recently reported that α 1 m can bind heme and that a C-terminally processed form of α 1 m degrades heme. It is shown here that α 1 m has catalytic reductase and NADH-dehydrogenase-like activities. Cytochrome c, nitroblue tetrazolium (NBT), methemoglobin and ferricyanide were reduced by α 1 m. Comparison of the reduction rates suggests that methemoglobin is a better substrate than cytochrome c, NBT and ferricyanide. The reactions with cytochrome c and NBT were mediated by superoxide anions since they were inhibited by superoxide dismutase. The addition of the biological electron donors NADH, NADPH or ascorbate enhanced the reduction rate of cytochrome c approximately 30-fold. Recombinant α 1 m, which has much less chromophore than plasma and urine α 1 m, was a stronger reductant than the latter α 1 m-forms. Site-directed mutagenesis of C34, K92, K118 and K130 and thiol group chemistry showed that the C34 thiol group was involved in the redox reaction but relies upon co-operation with the lysyl residues. The redox properties of α 1 m may provide a physiological protection mechanism against extracellularly exposed heme-groups and other oxidants.

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Plasma retinol binding protein: structure and function of the prototypic lipocalin

Cited by 158 publications

References 33 publications

RBP4: a controversial adipokine

RBP4: a controversial adipokine

An Essential Ligand-binding Domain in the Membrane Receptor for Retinol-binding Protein Revealed by Large-scale Mutagenesis and a Human Polymorphism

Redox properties of the lipocalin α1-microglobulin: Reduction of cytochrome c, hemoglobin, and free iron

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