Nutrients

Editorial

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3 pages, 174 KiB

Open AccessEditorial

Retinoic Acid: The Autacoid for All Seasons

by Joseph L. Napoli

Nutrients 2022, 14(21), 4526; https://doi.org/10.3390/nu14214526 - 27 Oct 2022

Cited by 5 | Viewed by 1747

Abstract

All-trans-retinoic acid (RA), a metabolite of vitamin A (retinol), exerts profuse actions that enable multiple aspects of reproduction, embryonic development and post-natal regulation of energy metabolism, glucoregulatory control, organ function, and of the skeletal, immune, nervous and cardiovascular systems, as well as cell [...] Read more.

All-trans-retinoic acid (RA), a metabolite of vitamin A (retinol), exerts profuse actions that enable multiple aspects of reproduction, embryonic development and post-natal regulation of energy metabolism, glucoregulatory control, organ function, and of the skeletal, immune, nervous and cardiovascular systems, as well as cell proliferation vs [...] Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

Research

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18 pages, 4966 KiB

Open AccessArticle

Mice Lacking the Systemic Vitamin A Receptor RBPR2 Show Decreased Ocular Retinoids and Loss of Visual Function

by Rakesh Radhakrishnan, Matthias Leung, Heidi Roehrich, Stephen Walterhouse, Altaf A. Kondkar, Wayne Fitzgibbon, Manas R. Biswal and Glenn P. Lobo

Nutrients 2022, 14(12), 2371; https://doi.org/10.3390/nu14122371 - 8 Jun 2022

Cited by 7 | Viewed by 2742

Abstract

The systemic transport of dietary vitamin A/all-trans retinol bound to RBP4 into peripheral tissues for storage is an essential physiological process that continuously provides visual chromophore precursors to the retina under fasting conditions. This mechanism is critical for phototransduction, photoreceptor cell maintenance [...] Read more.

The systemic transport of dietary vitamin A/all-trans retinol bound to RBP4 into peripheral tissues for storage is an essential physiological process that continuously provides visual chromophore precursors to the retina under fasting conditions. This mechanism is critical for phototransduction, photoreceptor cell maintenance and survival, and in the support of visual function. While the membrane receptor STRA6 facilitates the blood transport of lipophilic vitamin A into the eye, it is not expressed in most peripheral organs, which are proposed to express a second membrane receptor for the uptake of vitamin A from circulating RBP4. The discovery of a novel vitamin A receptor, RBPR2, which is expressed in the liver and intestine, but not in the eye, alluded to this long-sort non-ocular membrane receptor for systemic RBP4-ROL uptake and transport. We have previously shown in zebrafish that the retinol-binding protein receptor 2 (Rbpr2) plays an important role in the transport of yolk vitamin A to the eye. Mutant rbpr2 zebrafish lines manifested in decreased ocular retinoid concentrations and retinal phenotypes. To investigate a physiological role for the second vitamin A receptor, RBPR2, in mammals and to analyze the metabolic basis of systemic vitamin A transport for retinoid homeostasis, we established a whole-body Rbpr2 knockout mouse (Rbpr2^−/−) model. These mice were viable on both vitamin A-sufficient and -deficient diets. Rbpr2^−/− mice that were fed a vitamin A-sufficient diet displayed lower ocular retinoid levels, decreased opsins, and manifested in decrease visual function, as measured by electroretinography. Interestingly, when Rbpr2^−/− mice were fed a vitamin A-deficient diet, they additionally showed shorter photoreceptor outer segment phenotypes, altogether manifesting in a significant loss of visual function. Thus, under conditions replicating vitamin A sufficiency and deficiency, our analyses revealed that RBPR2-mediated systemic vitamin A transport is a regulated process that is important for vitamin A delivery to the eye when RBP4-bound ROL is the only transport pathway in the fasting condition or under vitamin A deficiency conditions. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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18 pages, 2334 KiB

Open AccessArticle

CRABPs Alter all-trans-Retinoic Acid Metabolism by CYP26A1 via Protein-Protein Interactions

by King Clyde B. Yabut and Nina Isoherranen

Nutrients 2022, 14(9), 1784; https://doi.org/10.3390/nu14091784 - 24 Apr 2022

Cited by 11 | Viewed by 3057

Abstract

Cellular retinoic acid binding proteins (CRABP1 and CRABP2) bind all-trans-retinoic acid (atRA), the active metabolite of vitamin A, with high affinity. CRABP1 and CRABP2 have been shown to interact with the atRA-clearing cytochrome P450 enzymes CYP26B1 and CYP26C1 and [...] Read more.

Cellular retinoic acid binding proteins (CRABP1 and CRABP2) bind all-trans-retinoic acid (atRA), the active metabolite of vitamin A, with high affinity. CRABP1 and CRABP2 have been shown to interact with the atRA-clearing cytochrome P450 enzymes CYP26B1 and CYP26C1 and with nuclear retinoic acid receptors (RARs). We hypothesized that CRABP1 and CRABP2 also alter atRA metabolism and clearance by CYP26A1, the third key atRA-metabolizing enzyme in the CYP26 family. Based on stopped-flow experiments, atRA bound CRABP1 and CRABP2 with K_d values of 4.7 nM and 7.6 nM, respectively. The unbound atRA K_m values for 4-OH-atRA formation by CYP26A1 were 4.7 ± 0.8 nM with atRA, 6.8 ± 1.7 nM with holo-CRABP1 and 6.1 ± 2.7 nM with holo-CRABP2 as a substrate. In comparison, the apparent k_cat value was about 30% lower (0.71 ± 0.07 min⁻¹ for holo-CRABP1 and 0.75 ± 0.09 min⁻¹ for holo-CRABP2) in the presence of CRABPs than with free atRA (1.07 ± 0.08 min⁻¹). In addition, increasing concentrations in apo-CRABPs decreased the 4-OH-atRA formation rates by CYP26A1. Kinetic analyses suggest that apo-CRABP1 and apo-CRABP2 inhibit CYP26A1 (K_i = 0.39 nM and 0.53 nM, respectively) and holo-CRABPs channel atRA for metabolism by CYP26A1. These data suggest that CRABPs play a critical role in modulating atRA metabolism and cellular atRA concentrations. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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24 pages, 3310 KiB

Open AccessArticle

Transcriptional Profiling of the Small Intestine and the Colon Reveals Modulation of Gut Infection with Citrobacter rodentium According to the Vitamin A Status

by Zhi Chai, Yafei Lyu, Qiuyan Chen, Cheng-Hsin Wei, Lindsay M. Snyder, Veronika Weaver, Aswathy Sebastian, István Albert, Qunhua Li, Margherita T. Cantorna and Catharine Ross

Nutrients 2022, 14(8), 1563; https://doi.org/10.3390/nu14081563 - 8 Apr 2022

Cited by 2 | Viewed by 4868

Abstract

Vitamin A (VA) deficiency and diarrheal diseases are both serious public health issues worldwide. VA deficiency is associated with impaired intestinal barrier function and increased risk of mucosal infection-related mortality. The bioactive form of VA, retinoic acid, is a well-known regulator of mucosal [...] Read more.

Vitamin A (VA) deficiency and diarrheal diseases are both serious public health issues worldwide. VA deficiency is associated with impaired intestinal barrier function and increased risk of mucosal infection-related mortality. The bioactive form of VA, retinoic acid, is a well-known regulator of mucosal integrity. Using Citrobacter rodentium-infected mice as a model for diarrheal diseases in humans, previous studies showed that VA-deficient (VAD) mice failed to clear C. rodentium as compared to their VA-sufficient (VAS) counterparts. However, the distinct intestinal gene responses that are dependent on the host’s VA status still need to be discovered. The mRNAs extracted from the small intestine (SI) and the colon were sequenced and analyzed on three levels: differential gene expression, enrichment, and co-expression. C. rodentium infection interacted differentially with VA status to alter colon gene expression. Novel functional categories downregulated by this pathogen were identified, highlighted by genes related to the metabolism of VA, vitamin D, and ion transport, including improper upregulation of Cl⁻ secretion and disrupted HCO₃⁻ metabolism. Our results suggest that derangement of micronutrient metabolism and ion transport, together with the compromised immune responses in VAD hosts, may be responsible for the higher mortality to C. rodentium under conditions of inadequate VA. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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13 pages, 1543 KiB

Open AccessFeature PaperArticle

Plasma Retinoid Concentrations Are Altered in Pregnant Women

by Lindsay C. Czuba, Emily E. Fay, Jeffrey LaFrance, Chase K. Smith, Sara Shum, Sue L. Moreni, Jennie Mao, Nina Isoherranen and Mary F. Hebert

Nutrients 2022, 14(7), 1365; https://doi.org/10.3390/nu14071365 - 25 Mar 2022

Cited by 8 | Viewed by 3421

Abstract

Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women ( [...] Read more.

Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25–28 weeks gestation and 28–32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25–28 weeks gestation, plasma retinol (−27%), 4-oxo-13-cis-retinoic acid (−34%), and albumin (−22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28–32 weeks gestation, plasma retinol (−41%), retinol binding protein 4 (RBP4; −17%), transthyretin (TTR; −21%), albumin (−26%), 13-cis-retinoic acid (−23%) and 4-oxo-13-cis-retinoic acid (−48%) concentrations were significantly lower, whereas plasma all-trans-retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans-retinoic acid concentrations are higher than postpartum. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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Review

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12 pages, 1244 KiB

Open AccessReview

Vitamin A in Skin and Hair: An Update

by Christine A. VanBuren and Helen B. Everts

Nutrients 2022, 14(14), 2952; https://doi.org/10.3390/nu14142952 - 19 Jul 2022

Cited by 21 | Viewed by 14878

Abstract

Vitamin A is a fat-soluble micronutrient necessary for the growth of healthy skin and hair. However, both too little and too much vitamin A has deleterious effects. Retinoic acid and retinal are the main active metabolites of vitamin A. Retinoic acid dose-dependently regulates [...] Read more.

Vitamin A is a fat-soluble micronutrient necessary for the growth of healthy skin and hair. However, both too little and too much vitamin A has deleterious effects. Retinoic acid and retinal are the main active metabolites of vitamin A. Retinoic acid dose-dependently regulates hair follicle stem cells, influencing the functioning of the hair cycle, wound healing, and melanocyte stem cells. Retinoic acid also influences melanocyte differentiation and proliferation in a dose-dependent and temporal manner. Levels of retinoids decline when exposed to ultraviolet irradiation in the skin. Retinal is necessary for the phototransduction cascade that initiates melanogenesis but the source of that retinal is currently unknown. This review discusses new research on retinoids and their effects on the skin and hair. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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14 pages, 3271 KiB

Open AccessReview

Actions of Retinoic Acid in the Pathophysiology of HIV Infection

by Neil Sidell and Maureen A. Kane

Nutrients 2022, 14(8), 1611; https://doi.org/10.3390/nu14081611 - 12 Apr 2022

Cited by 5 | Viewed by 2817

Abstract

The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA [...] Read more.

The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Here, we discuss the potential link between the roles played by RA in shaping intestinal immune responses and the manifestations and pathogenesis of HIV-associated enteropathy and similar conditions observed in SIV-infected non-human primate models. We also present data demonstrating the ability of RA to enhance the activation of replication-competent viral reservoirs from subjects on suppressive anti-retroviral therapy. The data suggest that retinoid supplementation may be a useful adjuvant for countering the pathologic condition of the gastro-intestinal tract associated with HIV infection and as part of a strategy for reactivating viral reservoirs as a means of depleting latent viral infection. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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22 pages, 3666 KiB

Open AccessReview

Retinoic Acid: Sexually Dimorphic, Anti-Insulin and Concentration-Dependent Effects on Energy

by Joseph L. Napoli

Nutrients 2022, 14(8), 1553; https://doi.org/10.3390/nu14081553 - 8 Apr 2022

Cited by 12 | Viewed by 3744

Abstract

This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities—especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This [...] Read more.

This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities—especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This report will introduce RA homeostasis and hormesis to provide context. Essential context also will encompass RA effects on adiposity, muscle function and pancreatic islet development and maintenance. These comments provide background for explaining interactions among insulin, glucagon and cortisol with RA homeostasis and function. One aim would clarify the often apparent RA contradictions related to pancreagenesis vs. pancreas hormone functions. The discussion also will explore the adverse effects of RA on estrogen action, in contrast to the enhancing effects of estrogen on RA action, the adverse effects of androgens on RA receptors, and the RA induction of androgen biosynthesis. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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15 pages, 1916 KiB

Open AccessFeature PaperReview

CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

by Jennifer Nhieu, Yu-Lung Lin and Li-Na Wei

Nutrients 2022, 14(7), 1528; https://doi.org/10.3390/nu14071528 - 6 Apr 2022

Cited by 16 | Viewed by 4841

Abstract

In this review, we discuss the emerging role of Cellular Retinoic Acid Binding Protein 1 (CRABP1) as a mediator of non-canonical activities of retinoic acid (RA) and relevance to human diseases. We first discuss the role of CRABP1 in regulating MAPK activities and [...] Read more.

In this review, we discuss the emerging role of Cellular Retinoic Acid Binding Protein 1 (CRABP1) as a mediator of non-canonical activities of retinoic acid (RA) and relevance to human diseases. We first discuss the role of CRABP1 in regulating MAPK activities and its implication in stem cell proliferation, cancers, adipocyte health, and neuro-immune regulation. We then discuss an additional role of CRABP1 in regulating CaMKII activities, and its implication in heart and motor neuron diseases. Through molecular and genetic studies of Crabp1 knockout (CKO) mouse and culture models, it is established that CRABP1 forms complexes with specific signaling molecules to function as RA-regulated signalsomes in a cell context-dependent manner. Gene expression data and CRABP1 gene single nucleotide polymorphisms (SNPs) of human cancer, neurodegeneration, and immune disease patients implicate the potential association of abnormality in CRABP1 with human diseases. Finally, therapeutic strategies for managing certain human diseases by targeting CRABP1 are discussed. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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24 pages, 1462 KiB

Open AccessReview

Retinoids in the Pathogenesis and Treatment of Liver Diseases

by Marta Melis, Xiao-Han Tang, Steven E. Trasino and Lorraine J. Gudas

Nutrients 2022, 14(7), 1456; https://doi.org/10.3390/nu14071456 - 31 Mar 2022

Cited by 13 | Viewed by 4988

Abstract

Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, [...] Read more.

Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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10 pages, 1278 KiB

Open AccessReview

Carotenoids, β-Apocarotenoids, and Retinoids: The Long and the Short of It

by Earl H. Harrison

Nutrients 2022, 14(7), 1411; https://doi.org/10.3390/nu14071411 - 28 Mar 2022

Cited by 19 | Viewed by 4421

Abstract

Naturally occurring retinoids (retinol, retinal, retinoic acid, retinyl esters) are a subclass of β-apocarotenoids, defined by the length of the polyene side chain. Provitamin A carotenoids are metabolically converted to retinal (β-apo-15-carotenal) by the enzyme β-carotene-15,15′-dioxygenase (BCO1) that catalyzes the oxidative cleavage of [...] Read more.

Naturally occurring retinoids (retinol, retinal, retinoic acid, retinyl esters) are a subclass of β-apocarotenoids, defined by the length of the polyene side chain. Provitamin A carotenoids are metabolically converted to retinal (β-apo-15-carotenal) by the enzyme β-carotene-15,15′-dioxygenase (BCO1) that catalyzes the oxidative cleavage of the central C=C double bond. A second enzyme β-carotene-9′-10′-dioxygenase cleaves the 9′,10′ bond to yield β-apo-10′-carotenal and β-ionone. Chemical oxidation of the other double bonds leads to the generation of other β-apocarotenals. Like retinal, some of these β-apocarotenals are metabolically oxidized to the corresponding β-apocarotenoic acids or reduced to the β-apocarotenols, which in turn are esterified to β-apocarotenyl esters. Other metabolic fates such as 5,6-epoxidation also occur as for retinoids. Whether the same enzymes are involved remains to be understood. β-Apocarotenoids occur naturally in plant-derived foods and, therefore, are present in the diet of animals and humans. However, the levels of apocarotenoids are relatively low, compared with those of the parent carotenoids. Moreover, human studies show that there is little intestinal absorption of intact β-apocarotenoids. It is possible that they are generated in vivo under conditions of oxidative stress. The β-apocarotenoids are structural analogs of the naturally occurring retinoids. As such, they may modulate retinoid metabolism and signaling. In deed, those closest in size to the C-20 retinoids—namely, β-apo-14′-carotenoids (C-22) and β-apo-13-carotenone (C-18) bind with high affinity to purified retinoid receptors and function as retinoic acid antagonists in transactivation assays and in retinoic acid induction of target genes. The possible pathophysiologic relevance in human health remains to be determined. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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30 pages, 1745 KiB

Open AccessReview

Mechanisms of Feedback Regulation of Vitamin A Metabolism

by Catherine O’Connor, Parisa Varshosaz and Alexander R. Moise

Nutrients 2022, 14(6), 1312; https://doi.org/10.3390/nu14061312 - 21 Mar 2022

Cited by 30 | Viewed by 6917

Abstract

Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental [...] Read more.

Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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8 pages, 525 KiB

Open AccessReview

Function of Retinoic Acid in Development of Male and Female Gametes

by M. Christine Schleif, Shelby L. Havel and Michael D. Griswold

Nutrients 2022, 14(6), 1293; https://doi.org/10.3390/nu14061293 - 18 Mar 2022

Cited by 19 | Viewed by 3977

Abstract

Retinoic acid, an active metabolite of vitamin A, is necessary for many developmental processes in mammals. Much of the field of reproduction has looked toward retinoic acid as a key transcriptional regulator and catalyst of differentiation events. This review focuses on the effects [...] Read more.

Retinoic acid, an active metabolite of vitamin A, is necessary for many developmental processes in mammals. Much of the field of reproduction has looked toward retinoic acid as a key transcriptional regulator and catalyst of differentiation events. This review focuses on the effects of retinoic acid on male and female gamete formation and regulation. Within spermatogenesis, it has been well established that retinoic acid is necessary for the proper formation of the blood–testis barrier, spermatogonial differentiation, spermiation, and assisting in meiotic completion. While many of the roles of retinoic acid in male spermatogenesis are known, investigations into female oogenesis have provided differing results. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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24 pages, 1411 KiB

Open AccessFeature PaperReview

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

by Julia S. Steinhoff, Achim Lass and Michael Schupp

Nutrients 2022, 14(6), 1236; https://doi.org/10.3390/nu14061236 - 15 Mar 2022

Cited by 29 | Viewed by 8113

Abstract

Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association [...] Read more.

Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations. Full article

(This article belongs to the Special Issue Recent Retinoid Research: Implications for Human Health)

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