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Background: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols)., Methods: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study., Results: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10 -6 ). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity., Conclusions: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern., (© 2024. The Author(s).)

Vitamin A is an important nutrient for multiple physiological functions. To elucidate the role of vitamin A in vivo, vitamin A-deficient diets have been often used in mice to establish a vitamin A-deficiency model. However, the information on the appropriate feeding periods and time course of changes in vitamin A content in organs after the start of vitamin A-deficient diet feeding is lacking. This study aimed to assess the retinoids levels in liver and white adipose tissue in mice fed a vitamin A-deficient diet for ≤8 weeks. High-performance liquid chromatography was used to measure the retinoids levels in liver and white adipose tissue every 2 weeks for ≤8 weeks. Vitamin A-deficient diet feeding significantly decreased retinol in the liver over 6 weeks, but retinyl palmitate, a main storage form of vitamin A, was not changed over 8 weeks. The plasma retinol level remained constant throughout the experiment. In white adipose tissue, retinyl palmitate gradually decreased over 8 weeks. These results indicate that vitamin A-deficient diet feeding longer than 6 weeks reduced retinol in liver and retinyl palmitate in white adipose tissue over 8 weeks, although it is not enough for the induction of a whole-body vitamin A deficiency.

Introduction: Chronic exposure to ultraviolet light photoages skin. Retinol, a precursor molecule to retinoic acid that causes less irritation, is available as a nonprescription, cosmetic retinoid and improves collagen production, skin elasticity, and signs of photoaging. Advances in formulation science have allowed the production of stabilized bioactive retinol formulations. This integrated analysis aims to build on previous studies and further examine the comprehensive efficacy and tolerability of topical 0.1% stabilized bioactive retinol., Methods: This analysis included 6 vehicle-controlled studies of 0.1% stabilized bioactive retinol in women with mild-to-moderate signs of photodamage. Across all studies, the same dermatologist investigator assessed overall photodamage; wrinkles on the forehead, cheeks, and undereye area; crow&rsquo;s feet wrinkles and fine lines; lack of even skin tone; and brown spots at baseline and weeks 4, 8, and 12 on a numerical scale. Tolerability was also assessed., Results: Participants (retinol, N=237; vehicle, N=234) had a mean (SD) age of 47.4 (6.6) years. Retinol induced greater improvements from baseline in all signs of photoaging vs vehicle as early as week 4 and through 12 weeks of application. Few participants experienced irritation; all events were mild to moderate and transient. The most common signs of irritation were erythema (n=2) and skin scaling/peeling (n=5)., Conclusions: This pooled analysis of 6 vehicle-controlled clinical studies provides new evidence for the efficacy of 0.1% stabilized bioactive retinol in improving signs of photoaging without causing major irritation. Topical 0.1% stabilized bioactive retinol was well tolerated with only a few reported cases of skin irritation. J Drugs Dermatol. 2024;23(4):&nbsp; &nbsp; &nbsp;doi:10.36849/JDD.8124.

In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 10 7 M -1 s -1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4-1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules., Competing Interests: The authors declare no conflicts. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The striatum is a brain structure involved in the control of voluntary movement. Striatum contains high amounts of retinoic acid, the active metabolite of vitamin A, as well as retinoid receptors, RARβ and RXRγ. Previous studies revealed that disruption of retinoid signaling initiated during development is deleterious for striatal physiology and related motor functions. However, the alteration of retinoid signaling, and the importance of vitamin A supply during adulthood on striatal physiology and function has never been established. In the present study, we investigated the impact of vitamin A supply on striatal function. Adult Sprague-Dawley rats were fed with three specific diets, either sub-deficient, sufficient, or enriched in vitamin A (0.4, 5, and 20 international units [IU] of retinol per g of diet, respectively) for 6 months. We first validated that vitamin A sub-deficient diet in adult rats constitutes a physiological model of retinoid signaling reduction in the striatum. We then revealed subtle alterations of fine motor skills in sub-deficient rats using a new behavioral apparatus specifically designed to test forepaw reach-and-grasp skills relying on striatal function. Finally, we showed using qPCR analysis and immunofluorescence that the striatal dopaminergic system per se was not affected by vitamin A sub-deficiency at adult age. Rather, cholinergic synthesis in the striatum and μ-opioid receptor expression in striosomes sub-territories were the most affected by vitamin A sub-deficiency starting at adulthood. Taken together these results revealed that retinoid signaling alteration at adulthood is associated with motor learning deficits together with discrete neurobiological alterations in the striatum., (© 2023 Federation of American Societies for Experimental Biology.)

Excessive hepatic lipid accumulation is a common phenomenon in cultured fish; however, its underlying mechanisms are poorly understood. Lipid droplet (LD)-related proteins play vital roles in LD accumulation. Herein, using a zebrafish liver cell line (ZFL), we show that LD accumulation is accompanied by differential expression of seven LD-annotated genes, among which the expression of dehydrogenase / reductase ( SDR family ) member 3 a / b ( dhrs3a / b ) increased synchronously. RNAi-mediated knockdown of dhrs3a delayed LD accumulation and downregulated the mRNA expression of peroxisome proliferator-activated receptor gamma ( pparg ) in cells incubated with fatty acids. Notably, Dhrs3 catalyzed retinene to retinol, the content of which increased in LD-enriched cells. The addition of exogenous retinyl acetate maintained LD accumulation only in cells incubated in a lipid-rich medium. Correspondingly, exogenous retinyl acetate significantly increased pparg mRNA expression levels and altered the lipidome of the cells by increasing the phosphatidylcholine and triacylglycerol contents and decreasing the cardiolipin, phosphatidylinositol, and phosphatidylserine contents. Administration of LW6, an hypoxia-inducible factor 1α (HIF1α) inhibitor, reduced the size and number of LDs in ZFL cells and attenuated hif1αa , hif1αb , dhrs3a , and pparg mRNA expression levels. We propose that the Hif-1α/Dhrs3a pathway participates in LD accumulation in hepatocytes, which induces retinol formation and the Ppar-γ pathway.

Our objective was to study the effect of differing dietary crude protein and vitamin A on retinoid metabolism in a periparturient rat model. Sixty female rats, approximately 21 d before parturition, were fed rations containing either low protein (13%; LP) or high protein (22%; HP) crude protein and either low vitamin A (3 IU/g; LA) or high vitamin A (5 IU/g; HA), yielding treatments HPHA, HPLA, LPHA, and LPLA. Samples were collected at d -14, d +3, and +10 relative to parturition and analyzed for all-trans retinoid acid (RA), 13-Cis RA, and retinol. At d -14, serum all-trans RA concentrations decreased compared to baseline. At both d +3 and d +10, serum retinol increased and liver 13-Cis RA decreased. In the small intestine, 13-cis RA was higher in HPHA than HPLA pre-partum (0.93±0.12 vs. 0.40±0.12 ng/ml, P =0.04). Post-partum, 13-cis RA was lower in high vitamin HPHA and LPHA groups (0.35±0.06 and 0.38±0.06 ng/ml) than in low vitamin A HPLA and LPLA treatments (0.50±0.06 and 1.32±0.06 ng/ml, P <0.01). In rats fed LA diets, TNF-alpha expression tended to be lower in HPLA than LPLA groups on day +3 (0.69±0.34 vs 1.00±0.52, P =0.08), but not day +10 (0.56±0.25 vs. 1.00±0.49 fold change, P >0.10). Retinoids accumulated during pregnancy and were mobilized during lactation. The sequestration of retinoids was increased when dietary protein content was low. Further studies are needed to investigate how retinoid metabolism could be manipulated to improve vitamin A delivery to milk.

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as " ABCA4 -retinopathies." Recent research has revealed that ABCA4 is expressed in other cells as well, such as hair follicles and keratinocytes, although no information on its significance has been evidenced so far. In this study, we investigated the role of the ABCA4 gene in human keratinocytes and hair follicle stem cells for the first time. We have shown that silencing the ABCA4 gene increases the deleterious effect of all-trans-retinal on human hair follicle stem cells.

The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty-seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3-hydroxymorphinan (3HM), were determined from a 2-hour post-dose plasma sample and cumulative 4-hour urine sample using liquid chromatography-mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P = .03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P = .04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P = .02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all-trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy., (© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Over the last decade, fluctuations of retinoids (RETs), also known as vitamin A and derivatives, have proved to be useful biomarkers to assess the environmental chemical pressure on a wide variety of non-target vertebrates. This use of RET-based biomarkers is of particular interest in the non-target sentinel species Gammarus fossarum in which RETs were shown to influence crucial physiological functions. To study and probe this metabolism in this crustacean model, a UHPLC-MS/MS method was developed to 1) identify and 2) monitor several endogenous RETs in unexposed females throughout their reproductive cycle. Then, females were exposed in controlled conditions to exogenous all-trans retinoic acid (atRA) and citral (CIT), a RA synthesis inhibitor, to simulate an excess or deficiency in RA. Perturbation of vitamin A metabolism by pesticides was further studied in response to methoprene (MET), a juvenile hormone analog as well as glyphosate (GLY). The developed method allowed, for the first time in this model, the identification of RA metabolites (all-trans 4-oxo and 13-cis 4-oxo RA), RA isomers (all-trans and 13-cis RA) as well as retinaldehyde (RALD) isomers (all-trans, 11-cis, and 13-cis RALD) and showed two distinct phases in the reproductive cycle. Retinoic acid successfully increased the tissular concentration of both RA isomers and CIT proved to be efficient at perturbating the conversion from RALD to RA. Methoprene perturbed the ratios between RA isomers whereas GLY had no observed effects on the RET system of G. fossarum females. We were able to discriminate different dynamics of RET perturbations by morphogens (atRA or CIT) or MET which highlights the plausible mediation of RETs in MET-induced disorders. Ultimately, our study shows that RETs are influenced by exposure to MET and strengthen their potential to assess aquatic ecosystem chemical status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The eye is an ideal organ for imaging by a multi-photon excitation approach, because ocular tissues such as the sclera, cornea, lens and neurosensory retina, are highly transparent to infrared (IR) light. The interface between the retina and the retinal pigment epithelium (RPE) is especially informative, because it reflects the health of the visual (retinoid) cycle and its changes in response to external stress, genetic manipulations, and drug treatments. Vitamin A-derived retinoids, like retinyl esters, are natural fluorophores that respond to multi-photon excitation with near IR light, bypassing the filter-like properties of the cornea, lens, and macular pigments. Also, during natural aging some retinoids form bisretinoids, like diretinoid-pyridiniumethanolamine (A2E), that are highly fluorescent. These bisretinoids appear to be elevated concurrently with aging. Vitamin A-derived retinoids and bisretinoidss are detected by two-photon ophthalmoscopy (2PO), using a new class of light sources with adjustable spatial, temporal, and spectral properties. Furthermore, the two-photon (2P) absorption of IR light by the visual pigments in rod and cone photoreceptors can initiate visual transduction by cis-trans isomerization of retinal, enabling parallel functional studies. Recently we overcame concerns about safety, data interpretation and complexity of the 2P-based instrumentation, the major roadblocks toward advancing this modality to the clinic. These imaging and retina-function assessment advancements have enabled us to conduct the first 2P studies with humans., Competing Interests: Declaration of competing interest K.P. is the Chief Scientific Officer of Polgenix Inc., and a consultant for Editas Medicine. K.P. is Chief Scientific Officer at Polgenix, Inc. K.P. is an inventor of U.S. patents 7,706,863 and 8,346,345, whose values may be affected by this publication. G.P. is an employee of Polgenix, Inc. M.W. declared no conflict of interest exists., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This Perspective discusses how retinol catalyzes resonance energy transfer (RET) reactions pivotally important for mitochondrial energy homeostasis by protein kinase C δ (PKCδ). PKCδ signals to the pyruvate dehydrogenase complex, controlling oxidative phosphorylation. The PKCδ-retinol complex reversibly responds to the redox potential of cytochrome c, that changes with the electron transfer chain workload. In contrast, the natural retinoid anhydroretinol irreversibly activates PKCδ. Its elongated conjugated-double-bond system limits the energy quantum absorbed by RET. Consequently, while capable of triggering the exergonic activating pathway, anhydroretinol fails to activate the endergonic silencing path, trapping PKCδ in the ON position and causing harmful levels of reactive oxygen species. However, physiological retinol levels displace anhydroretinol, buffer cyotoxicity and potentially render anhydroretinol useful for rapid energy generation. Intriguingly, apocarotenoids, the primary products of the mitochondrial β-carotene,9'-10'-oxygenase, have all the anhydroretinol-like features, including modulation of energy homeostasis. We predict significant conceptual advances to stem from further understanding of the retinoid-catalyzed RET., (© 2023. The Author(s).)

Retinoids and vitamin A are essential for multiple biological functions, including vision and immune responses, as well as the development of an embryo during pregnancy. Despite its importance, alterations in retinoid homeostasis during normal human pregnancy are incompletely understood. We aimed to characterize the temporal changes in the systemic retinoid concentrations across pregnancy and postpartum period. Monthly blood samples were collected from twenty healthy pregnant women, and plasma concentrations of retinol, all-trans-retinoic acid (atRA), 13-cis-retinoic acid (13cisRA), and 4-oxo-retinoic acids were measured using liquid chromatography-tandem mass spectrometry. Significant decreases in 13cisRA concentrations over the pregnancy were observed, with rebound increases in retinol and 13cisRA levels after delivery. Of note, atRA concentrations exhibited a unique temporal pattern with levels peaking at mid-pregnancy. While the 4-oxo-atRA concentration was below the limit of quantification, 4-oxo-13cisRA was readily detectable, and its temporal change mimicked that of 13cisRA. The time profiles of atRA and 13cisRA remained similar after correction by albumin levels for plasma volume expansion adjustment. Together, the comprehensive profiling of systemic retinoid concentrations over the course of pregnancy provides insights into pregnancy-mediated changes in retinoid disposition to maintain its homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jeong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bakuchiol (BAK), a meroterpene phenol abundant in the plant Psoralea corylifolia, is an emerging cosmeceutical agent with promising anti-aging, anti-inflammatory, and antibacterial properties. The trend for "clean" skincare products and search for anti-aging retinoid alternatives have poised BAK as a "must-have" ingredient in skincare., Aims: Our aim was to review the data for the applications of BAK in dermatology., Methods: This is a systematic review of PubMed., Results: Thirty articles matched our search terms ["Bakuchiol" and "Dermatology"] or ["Bakuchiol" and "Skin"] of which one did not meet inclusion criteria, 16 were pre-clinical studies, seven clinical studies, three commentaries, two narrative reviews, and one report on adverse events. BAK has been mostly studied for its effects on photoaging, acne, and post-inflammatory hyperpigmentation (PIH), showing beneficial results comparable to those achieved by topical retinoids. While having no structural resemblance to retinoids, BAK can function as a retinol analog, through retinol-like regulation of gene expression. In in vivo studies, BAK was used alone or in combination with other products resulting in a significant reduction in photodamage, hyperpigmentation, wrinkle scores, and acne severity. Additionally, in vitro studies hinted at its anti-cancer properties by inhibiting epidermal growth factor induced neoplastic cell transformation. Also, demonstrated potential applications in psoriasis by normalizing keratinocyte activity and in pigmentary disorders through inhibition of melanogenesis. There was one adverse event case reported of contact dermatitis in the literature., Conclusions: Bakuchiol is a retinol alternative with anti-aging, antibacterial, and anti-inflammatory properties. Additional studies are warranted to better understand its applications in dermatology., (© 2022 Wiley Periodicals LLC.)

Efficient delivery of vitamin A to the retinal pigment epithelium is vital to the production of the light-sensitive visual chromophore 11-cis-retinal. Nevertheless, retinol binding protein 4 (RBP4) is the only known carrier of vitamin A in plasma. Here, we present new findings that further characterize the visual cycle in the presence of Rbp4 deficiency. In the face of impaired delivery of retinol in Rbp4 -/- mice, we determined that 11-cis-retinaldehyde reached levels that were ∼60% of WT at 4 months of age and all-trans-retinyl ester was 18% of normal yet photoreceptor cell loss was apparent by 8 months of age. The lack of Rbp4 appeared to have a greater impact on scotopic rod-mediated responses than on cone function at early ages. Also, despite severely impaired delivery of retinol, bisretinoid lipofuscin that forms as a byproduct of the visual cycle was measurable by HPLC and by quantitative fundus autofluorescence. In mice carrying an Rpe65 amino acid variant that slows visual cycle kinetics, Rbp4 deficiency had a less pronounced effect on 11-cis-retinal levels. Finally, we found that ocular retinoids were not altered in mice expressing elevated adipose-derived total Rbp4 protein (hRBP4 +/+ AdiCre +/- ). In conclusion, our findings are consistent with a model in which vitamin A can be delivered to the retina by Rbp4-independent pathways., Competing Interests: Conflicts of interest The authors declare that there are no conflicts of interest related to the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatocytes secrete retinol-binding protein 4 (RBP4) into circulation, thereby mobilizing vitamin A from the liver to provide retinol for extrahepatic tissues. Obesity and insulin resistance are associated with elevated RBP4 levels in the blood. However, in a previous study, we observed that chronically increased RBP4 by forced Rbp4 expression in the liver does not impair glucose homeostasis in mice. Here, we investigated the effects of an acute mobilization of hepatic vitamin A stores by hepatic overexpression of RBP4 in mice. We show that hepatic retinol mobilization decreases body fat content and enhances fat turnover. Mechanistically, we found that acute retinol mobilization increases hepatic expression and serum levels of fibroblast growth factor 21 (FGF21), which is regulated by retinol mobilization and retinoic acid in primary hepatocytes. Moreover, we provide evidence that the insulin-sensitizing effect of FGF21 is associated with organ-specific adaptations in retinoid homeostasis. Taken together, our findings identify a novel crosstalk between retinoid homeostasis and FGF21 in mice with acute RBP4-mediated retinol mobilization from the liver., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Retinol-binding protein 2 (RBP2, also known as cellular retinol-binding protein 2 (CRBP2)) is a member of the fatty acid-binding protein family and has been extensively studied for its role in facilitating dietary vitamin A (retinol) uptake and metabolism within enterocytes of the small intestine. RBP2 is present in highest concentrations in the proximal small intestine where it constitutes approximately 0.1-0.5% of soluble protein. Recent reports have established that RBP2 binds monoacylglycerols (MAGs) with high affinity, including the canonical endocannabinoid 2-arachidonoylglycerol (2-AG). Crystallographic studies reveal that retinol, 2-AG, or other long-chain MAGs alternatively can bind in the retinol-binding pocket of RBP2. It also has been demonstrated recently that Rbp2-deficient mice are more susceptible to developing obesity and associated metabolic phenotypes when exposed to a high fat diet, or as they age when fed a conventional chow diet. When subjected to an oral fat challenge, the Rbp2-deficient mice release into the circulation significantly more, compared to littermate controls, of the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP). These new findings regarding RBP2 structure and actions within the intestine are the focus of this review., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Vitamin A is distributed within the body to support chromophore synthesis in the eyes and retinoid signaling in most other tissues. Two pathways exist for the delivery of vitamin A: the extrinsic pathway transports dietary vitamin A in lipoproteins from intestinal enterocytes to tissues, while the intrinsic pathway distributes vitamin A from hepatic stores bound to serum retinol binding protein (RBP). Previously, the intestine-specific homeodomain transcription factor (ISX) and the RBP receptor STRA6 were identified as gatekeepers of these pathways; however, it is not clear how mutations in the corresponding genes affect retinoid homeostasis. Here, we used a genetic dissection approach in mice to examine the contributions of these proteins in select tissues. We observed that ISX deficiency increased utilization of both preformed and provitamin A. We found that increased storage of retinoids in peripheral tissues of ISX-deficient mice was dependent on STRA6 and induced by retinoid signaling. In addition, double-mutant mice exhibited a partial rescue of the Stra6 mutant ocular phenotype. This rescue came at the expense of a massive accumulation of vitamin A in other tissues, demonstrating that vitamin A is randomly distributed when present in excessive amounts. Remarkably, provitamin A supplementation of mutant mice induced the expression of the RBP receptor 2 in the liver and was accompanied by increased hepatic retinyl ester stores. Taken together, these findings indicate dynamic crosstalk between the delivery pathways for this essential nutrient and suggest that hepatic reuptake of vitamin A takes place when excessive amounts circulate in the blood., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

Macrophages are critical players in the development of atherosclerotic lesions, where they promote local and systemic inflammation. Macrophages engulf lipoproteins and cell debris upon entry into the arterial wall, becoming lipid-laden foam cells. While most lipids found in foam cells are triglyceride and cholesterol, these cells accumulate several other lipids with bioactive properties, such as vitamin A and carotenoids. Vitamin A has strong immunomodulatory actions in macrophages and other immune cells. For example, macrophages release vitamin A as retinoic acid to modulate T cell differentiation, but the implication of intracellular vitamin A stores in this process remains elusive due to the lack of an adequate experimental model to load vitamin A into macrophages. The purpose of this study was to develop a reliable method to deliver vitamin A to cultured murine macrophages. Our results show that thioglycolate-elicited peritoneal macrophages fail to take up significant levels of vitamin A when provided as free retinol. Cultured macrophages and macrophages in the peritoneal cavity can take up retinyl esters, either as retinyl ester-loaded serum or retinyl esters infused directly into the peritoneal cavity. HPLC analyses in macrophage lysates revealed that the intraperitoneal injection method results in a fourfold greater vitamin A loading efficiency than retinyl ester-loaded serum added to cultured cells. These two alternative methods provide an efficient and reliable methodology to load macrophages with vitamin A for downstream applications such as studies of gene regulation trafficking of intracellular vitamin A, and vitamin A release from macrophages., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Vitamin A and carotenoids are fat-soluble micronutrients that play important role as powerful antioxidants modulating oxidative stress and cancer development. Breast cancer is the most common malignancy in women. As the risk of breast cancer is dependent on various lifestyle factors such as dietary modifications, there is increasing interest surrounding the anti-cancerous properties of vitamin A and carotenoids. Despite the suggested protective roles of vitamin A and carotenoids in breast cancer development, their clinical application for the prevention and treatment of breast cancer is limited. In this narrative review, we discuss the roles of vitamin A and carotenoids along with the evaluation method of vitamin A status. We also exhibit the association of genetic variations involved in metabolism of vitamin A and carotenoids with cancers and other diseases. We demonstrate the epidemiological evidence for the relationship of vitamin A and carotenoids with breast cancer risk, their effects on cancer mechanism, and the recent updates in clinical practice of vitamin A or carotenoids as a potential therapeutic agent against breast cancer. This review provides insight into the preventive and therapeutic roles of vitamin A and carotenoids in breast cancer development and progression.

Objective: Vitamin A is commonly recommended as a treatment for diarrhea and undernutrition; however, little is known about the underlying cellular mechanisms. The aim of this study was to investigate the modulation of cell cycle by vitamin A derivatives (retinyl palmitate or retinol) in undernourished intestinal epithelial crypts (IEC-6)., Methods: IEC-6 cells were exposed to nutrient deprivation (no serum and no glutamine) and supplemented with retinyl palmitate or retinol at a range of 2 to 20 μM. Proliferation, apoptosis/necrosis, cell cycle process, and gene transcription were assessed., Results: Nutrient deprivation for 6, 12, 24, or 48 h decreased cell proliferation, and retinyl palmitate further decreased it after 24 and 48 h. Apoptosis rates were reduced by undernourishment and further reduced by retinyl palmitate after 48 h; whereas necrosis rates were unaltered. Undernourishment induced overall cell quiescence, increased percentage of cells in G0/G1 phase and decreased percentage of cells in S phase after 12 h and in G2/M phases at 6, 12, and 24 h after treatment. Both retinoids also showed cell quiescence induction with less cells in G2/M phases after 48 h, whereas only retinol showed significant modulation of G0/G1 and S phases. Both retinoids also increased markers of cell differentiation Fabp and Iap gene transcriptions in about fivefold rates after 42 h. Furthermore, specific gene transcriptions related to MAP kinase signaling pathway regulation of cell differentiation and cell cycle regulation were triggered by retinoids in undernourished IEC-6, with higher levels of expression for Atf2 and C-jun genes., Conclusions: These findings indicated that both vitamin A derivatives induce further survival mechanisms in undernourished intestinal epithelial crypt cells. These mechanisms include increased cell quiescence, decreased apoptosis, increased cell differentiation, and transcription of genes related to MAP kinase signaling pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.

Background: Retinol (RO) and its active metabolite retinoic acid (RA) are major regulators of gene expression in vertebrates and influence various processes like organ development, cell differentiation, and immune response. To characterize a general transcriptomic response to RA-exposure in vertebrates, independent of species- and tissue-specific effects, four publicly available RNA-Seq datasets from Homo sapiens, Mus musculus, and Xenopus laevis were analyzed. To increase species and cell-type diversity we generated RNA-seq data with chicken hepatocellular carcinoma (LMH) cells. Additionally, we compared the response of LMH cells to RA and RO at different time points., Results: By conducting a transcriptome meta-analysis, we identified three retinoic acid response core clusters (RARCCs) consisting of 27 interacting proteins, seven of which have not been associated with retinoids yet. Comparison of the transcriptional response of LMH cells to RO and RA exposure at different time points led to the identification of non-coding RNAs (ncRNAs) that are only differentially expressed (DE) during the early response., Conclusions: We propose that these RARCCs stand on top of a common regulatory RA hierarchy among vertebrates. Based on the protein sets included in these clusters we were able to identify an RA-response cluster, a control center type cluster, and a cluster that directs cell proliferation. Concerning the comparison of the cellular response to RA and RO we conclude that ncRNAs play an underestimated role in retinoid-mediated gene regulation.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed Ldlr -/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr -/- / Bco1 -/- mice despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Zhou et al.)

Objectives: Renal phosphate and vitamin D metabolism are regulated by proteohormone fibroblast growth factor 23 (FGF23), which is secreted by bone cells. FGF23 inhibits phosphate reabsorption and the production of calcitriol, active vitamin D (1,25(OH) 2 D 3 ). FGF23 generated by other cells exerts further paracrine effects in the liver, heart, and immune system. The FGF23 plasma concentration is positively associated with the onset and progression of kidney and cardiovascular diseases, disclosing FGF23 as a potential disease biomarker. The effects of vitamin A on the expression of FGF23 are controversial. Vitamin A components, retinoids, are mainly effective through nuclear retinoic acid receptors (RAR) and exert different effects on bone. The aim of this study was to clarify whether vitamin A modulates the production of FGF23., Methods: We studied the relevance of vitamin A for FGF23 production. Fgf23 transcripts were determined by real-time quantitative polymerase chain reaction in UMR106 osteoblast-like cells and IDG-SW3 osteocytes. FGF23 protein in the cell culture supernatant was measured by enzyme-linked immunosorbent assay., Results: All-trans-retinoic acid, retinyl acetate, RAR agonist TTNPB (4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid), and 13-cis-retinoic acid downregulated the expression of the Fgf23 gene in a dose-dependent manner. This effect was significantly attenuated by RAR antagonist AGN193109 (4-[2-[5,6-Dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl]benzoic acid)., Conclusion: The present study demonstrated that vitamin A is a potent suppressor of FGF23 production through RAR., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Vitamin A is an essential nutrient, critical for proper embryonic development in mammals. Both embryonic vitamin A-deficiency or -excess lead to congenital malformations or lethality in mammals, including humans. This is due to the defective transcriptional action of retinoic acid, the active form of vitamin A, that regulates in a spatial- and temporal-dependent manner the expression of genes essential for organogenesis. Thus, an adequate supply of vitamin A from the maternal circulation is vital for normal mammalian fetal development. Provitamin A carotenoids circulate in the maternal bloodstream and are available to the embryo. Of all the dietary carotenoids, β-carotene is the main vitamin A precursor, contributing at least 30% of the vitamin A intake in the industrialized countries and often constituting the sole source of retinoids (vitamin A and its derivatives) in the developing world. In humans, up to 40% of the absorbed dietary β-carotene is incorporated in its intact form in chylomicrons for distribution to other organs within the body, including the developing tissues. Here, it can serve as a source of vitamin A upon conversion into apocarotenoids by its cleavage enzymes. Given that β-carotene is carried in the bloodstream by lipoproteins, and that the placenta acquires, assembles and secretes lipoproteins, it is becoming evident that the maternal-fetal transfer of β-carotene relies on lipoprotein metabolism. Here, we will explore the current knowledge about this important biological process, the cross-talk between carotenoid and lipid metabolism in the context of the maternal-fetal transfer of this provitamin A precursor, and the mechanisms whereby β-carotene is metabolized by the developing tissues. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate that β-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linking these nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Three original cosmetic formulations containing retinol as an active component with liquid crystal, lamellar, and lipid bases were prepared. The formulas contain different concentrations of retinol, that is, 0.5%, 0.3%, and 0.15%., Objectives: The aim of the study was to evaluate a spectrophotometric method for assessing the quantity of retinol in the nine cosmetic products and to determine the viscosity of each formula., Materials and Methods: The formulations were tested for stability; final product testing was preceded by sample weighing and pH measurement as well as exposure to the light source from xenon lamp that maps solar radiation in the range of 310-800 nm. Microbiological purity test was performed according to the PN-EN ISO 29621:2011 method and viscosity carried out using a cone-plate digital rheometer (DV-III Brookfield, version 3.0) on 0.5 cm 3 emulsion samples at 32°C. The retinol content in preparations was assayed by UV spectrophotometry., Results: Each of prepared cosmetic products with retinol storing in a room temperature occurred to be stable. The liquid crystal emulsion has the higher viscosity than lamellar and lipid emulsions. Although the retinol concentration in lipid serum was determined with high accuracy, the method has some limitations associated with differences between the lipid cosmetic base and the lamellar and liquid crystal sera. Nevertheless, the UV spectrophotometric method described herein is a simple and highly accurate approach for determining the retinol content in lipid cosmetics: Its coefficient of correlation was R 2  = 0.9982 with a relative standard deviation (n = 3) in the range of 0.5%-1.5%., Conclusion: The presented UV spectrophotometric method represents an effective tool for fast and accurate determination of retinol content in lipid formulations. Probably, the method could be used in studies of other retinol-based preparations, for example, medications, and for determining the effective life of retinol-containing products in storage., (© 2020 Wiley Periodicals, Inc.)

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.

Vitamin A and derivatives, the natural retinoids, underpin signaling pathways of cellular differentiation, and are key chromophores in vision. These functions depend on transfer across membranes, and carrier proteins to shuttle retinoids to specific cell compartments. Natural retinoids, ultimately derived from plant carotenoids by metabolism to all-trans retinol, are lipophilic and consist of a cyclohexenyl (β-ionone) moiety linked to a polyene chain. This structure constrains the orientation of retinoids within lipid membranes. Cis-trans isomerization at double bonds of the polyene chain and s-cis/s-trans rotational isomerization at single bonds define the functional dichotomy of retinoids (signaling/vision) and specificities of interactions with specific carrier proteins and receptors. Metabolism of all-trans retinol to 11-cis retinal, transfer to photoreceptors, and removal and recycling of all-trans retinal generated by photoreceptor irradiation, is the key process underlying vision. All-trans retinol transferred into cells is metabolized to all-trans retinoic acid and shuttled to the cell nucleus to regulate gene expression controlling organ, tissue and cell differentiation, and cellular homeostasis. Research methods need to address the potential of photoisomerization in vitro to confound research results, and data should be interpreted in the context of membrane-association properties of retinoids and physiological concentrations in vivo. Despite a century of research, there are many fundamental questions of retinoid cellular biochemistry and molecular biology still to be answered. Computational modeling techniques will have an important role for understanding the nuances of vitamin A signaling and function., (© 2020 Elsevier Inc. All rights reserved.)

Vitamin A deficiency studies have been carried out since the early 1900s. Initially, these studies led to the identification of fat soluble A as a unique and essential component of the diet of rodents, birds, and humans. Continuing work established that vitamin A deficiency produces biochemical and physiological dysfunction in almost every vertebrate organ system from conception to death. This chapter begins with a review of representative historical and current studies that used the nutritional vitamin A deficiency research model to gain an understanding of the many roles vitamin A plays in prenatal and postnatal development and well-being. This is followed by a discussion of recent studies that show specific effects of vitamin A deficiency on prenatal development and postnatal maintenance of the olfactory epithelium, brain, and heart. Vitamin A deficiency studies have helped define the necessity of vitamin A for the health of all vertebrates, including farm animals, but the breadth of deficient states and their individual effects on health have not been fully determined. Future work is needed to develop tools to assess the complete vitamin A status of an organism and to define the levels of vitamin A that optimally support molecular and systems level processes during all ages and stages of life.

Vitamin A signaling pathways are predominantly driven by the cellular concentrations of all-trans-retinoic acid (atRA), as the main mechanism of retinoid signaling is via activation of retinoic acid receptors. atRA concentrations are in turn controlled by the storage of vitamin A and enzymatic processes that synthesize and clear atRA. This has resulted in the need for robust and highly specific analytical methods to accurately quantify retinoids in diverse biological matrices. Tissue-specific differences in both the quantity of retinoids and background matrix interferences can confound the quantification of retinoids, and the bioanalysis requires high performance instrumentation, such as liquid chromatography mass-spectrometry (LC-MS). Successful bioanalysis of retinoids is further complicated by the innate structural instability of retinoids and their relatively high lipophilicity. Further, in vitro experiments with retinoids require attention to experimental design and interpretation to account for the instability of retinoids due to isomerization and degradation, sequential metabolism to numerous structurally similar metabolites, and substrate depletion during experiments. In addition, in vitro biological activity is often confounded by residual presence of retinoids in common biological reagents such as cell culture media. This chapter identifies common biological and analytical complexities in retinoid bioanalysis in diverse biological matrices, and in the use of retinoids in cell culture and metabolic incubations. In addition, this chapter highlights best practices for the successful detection and quantification of the vitamin A metabolome in a wide range of biological matrices., (© 2020 Elsevier Inc. All rights reserved.)

The placenta, a hallmark of mammalian embryogenesis, allows nutrients to be exchanged between the mother and the fetus. Vitamin A (VA), an essential nutrient, cannot be synthesized by the embryo, and must be acquired from the maternal circulation through the placenta. Our understanding of how this transfer is accomplished is still in its infancy. In this chapter, we recapitulate the early studies about the relationship between maternal dietary/supplemental VA intake and fetal VA levels. We then describe how the discovery of retinol-binding protein (RBP or RBP4), the development of labeling and detection techniques, and the advent of knockout mice shifted this field from a macroscopic to a molecular level. The most recent data indicate that VA and its derivatives (retinoids) and the pro-VA carotenoid, β-carotene, are transferred across the placenta by distinct proteins, some of which overlap with proteins involved in lipoprotein uptake. The VA status and dietary intake of the mother influence the expression of these proteins, creating feedback signals that control the uptake of retinoids and that may also regulate the uptake of lipids, raising the intriguing possibility of crosstalk between micronutrient and macronutrient metabolism. Many questions remain about the temporal and spatial patterns by which these proteins are expressed and transferred throughout gestation. The answers to these questions are highly relevant to human health, considering that those with either limited or excessive intake of retinoids/carotenoids during pregnancy may be at risk of obtaining improper amounts of VA that ultimately impact the development and health of their offspring.

Here, we tested a hypothesis that vitamin A and/or its metabolic pathways are involved in the high-fructose-mediated alteration in adipose tissue biology. For this purpose, weanling male Wistar rats were provided with one of the following diets: control (C), control with vitamin A deficiency (C-VAD), high fructose (HFr), and HFr with VAD (HFr-VAD) for 16 weeks, except that half of the C-VAD diet-fed rats were shifted to HFr diet (C-VAD(s)HFr), after 8-week period. Compared with control, feeding of HFr diet significantly increased the triglyceride content (P ≤ .01) and thus adipocyte size (hypertrophy) (P ≤ .001) in visceral adipose depot; retroperitoneal white adipose tissue (RPWAT) and these changes were corroborated with de novo lipogenesis, as evidenced by the increased glycerol-3-phosphate dehydrogenase activity (P ≤ .01) and up-regulation of lipogenic pathway transcripts, fructose transporter, and aldehyde dehydrogenase 1 A1. On the contrary, the absence of vitamin A in the HFr diet (HFr-VAD) failed to exert these changes; however, it induced adipocyte hyperplasia. Further, vitamin A deficiency-mediated changes were reversed by replenishment, as evident from the group that was shifted from C-VAD to HFr diet. In conclusion, vitamin A and its metabolic pathway play a key determinant role in the high-fructose-induced triglyceride accumulation and adipocyte hypertrophy of visceral white adipose depot. SIGNIFICANCE OF THE STUDY: Here, we report the metabolic impact of high-fructose feeding under vitamin A-sufficient and vitamin A-deficient conditions. Feeding of high-fructose diet induced triglyceride accumulation and adipocyte hypertrophy of the visceral white adipose depots. These changes corroborated with augmented expression of vitamin A and lipid metabolic pathway genes. Contrarily, absence of vitamin A in the high-fructose diet did not elicit such responses, while vitamin A replenishment reversed the changes exerted by vitamin A deficiency. To our knowledge, this is the first study to report the role of vitamin A and its metabolic pathway in the high-fructose-induced triglyceride synthesis and its accumulation in visceral adipose depot and thus provide a new insight and scope to understand these nutrients interaction in clinical conditions., (© 2019 John Wiley & Sons, Ltd.)

The skin is the largest epithelial surface protecting the body from invading microbes. Vitamin A plays vital roles in the host defence of the skin, including promoting epithelial cell integrity, proliferation, and differentiation and even mediating immune responses. Furthermore, vitamin A derivatives, retinoid drugs, are widely used to treat skin diseases, such as acne and psoriasis. However, the immunoregulatory mechanisms of retinoids in dermatology have not been systematically described. In this paper, we discuss the immunological functions of retinoids during disease treatment, especially in skin disorders caused by exogenous infections.

Vitamin A is a general term for retinoids. Vitamin A deficiency leads to a variety of cutaneous manifestations. It also functions as a hormone through retinoic acid receptors altering the activity of multiple cell lines. Pancreatic vitamin A levels are critical for retinoid signaling and normal pancreatic control of glucose. Vitamin A deficiency is more common during infection, and supplementation reduces severe morbidity and mortality from infectious diseases. Vitamin A modulates activities at the cellular level and, via its interrelationship with hormones such as thyroid, insulin, and corticosteroids, has diffuse metabolic effects on the body. It plays an important role in all stages of wound healing. Vitamin A is known for its ability to stimulate epithelial growth, fibroblasts, granulation tissue, angiogenesis, collagen synthesis, epithelialization, and fibroplasia. Local (topical) and systemic supplementation with vitamin A has been proven to increase dermal collagen deposition. There are numerous animal studies and limited human studies regarding physiologic effect of vitamin A on acute or chronic wounds via systemic or topical administration. The most common use of vitamin A supplementation is to offset steroids' effect. When considering supplementation, the potential benefits must be weighed against the risk of harm. Vitamin A toxicity can be critical and even result in death. The evidence for supplementation with vitamin A is currently limited to expert opinion and is not backed up by rigorous trials. There is an acute need for therapeutic trials with vitamin A supplementations., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Vitamin A is an essential micronutrient that comes in multiple forms, including retinols, retinals, and retinoic acids. Dietary vitamin A is absorbed as retinol from preformed retinoids or as pro-vitamin A carotenoids that are converted into retinol in the enterocyte. These are then delivered to the liver for storage via chylomicrons and later released into the circulation and to its biologically active tissues bound to retinol-binding protein. Vitamin A is a crucial component of many important and diverse biological functions, including reproduction, embryological development, cellular differentiation, growth, immunity, and vision. Vitamin A functions mostly through nuclear retinoic acid receptors, retinoid X receptors, and peroxisome proliferator-activated receptors. Retinoids regulate the growth and differentiation of many cell types within skin, and its deficiency leads to abnormal epithelial keratinization. In wounded tissue, vitamin A stimulates epidermal turnover, increases the rate of re-epithelialization, and restores epithelial structure. Retinoids have the unique ability to reverse the inhibitory effects of anti-inflammatory steroids on wound healing. In addition to its role in the inflammatory phase of wound healing, retinoic acid has been demonstrated to enhance production of extracellular matrix components such as collagen type I and fibronectin, increase proliferation of keratinocytes and fibroblasts, and decrease levels of degrading matrix metalloproteinases., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.

Vitamin A and its derivatives contribute to many physiological processes, including vision, neural differentiation, and reproduction. Vitamin A deficiency causes early cessation of spermatogenesis, characterized by a marked depletion of germ cells. However, there has been no clear understanding about the role of chronic intake of vitamin A excess (VAE) in spermatogenesis. The objective of this study was to investigate whether chronic intake of VAE diet causes arrest of spermatogenesis. To examine the effects of VAE on spermatogenesis, we used ICR male mice fed with control (AIN-93G purified diet: 4 IU/g) diet or VAE (modified AIN-93G diet with VAE: 1,000 IU/g) diet for 7 weeks (from 3 to 10 weeks of age). At 10 weeks of age, the retinol concentration in the testes of VAE mice was significantly higher than that of control mice. Testicular cross sections from control mice contained a normal array of germ cells, while the seminiferous tubules from VAE mice exhibited varying degrees of testicular degeneration. Daily sperm production in VAE testes was dramatically decreased compared to that in control testes. Sperm viability, motility, and morphology were also impaired in VAE mice. Furthermore, we examined the effects of VAE on the expression of genes involved in retinoid signaling and spermatogenesis to determine the underlying molecular mechanisms. Therefore, we are the first to present results describing the long-term dietary intake of VAE impairs spermatogenesis using a mouse model.

Benzo[a]pyrene (B[a]P) is one of the polycyclic aromatic hydrocarbons which is formed due to smoking of foods, incomplete combustion of woods, vehicle exhausts, and cigarettes smokes. B[a]P gets entry into human and animal bodies mainly through their diets. Metabolic activation of B[a]P is required to induce mutagenesis and carcinogenesis in animal and human studies. Carotenoids and retinoids are phytochemicals that if ingested have multiple physiological interferences in the human and animal bodies. In this study, we firstly investigated the protective effects of β-carotene, β-apo-8-carotenal, retinol, and retinoic acid against B[a]P-induced mutagenicity and oxidative stress in human HepG2 cells. Secondly, we tested the hypothesis of modulating xenobiotic metabolizing enzymes (XMEs) by carotenoids and retinoids as a possible mechanism of protection by these micronutrients against B[a]P adverse effects. The obtained results declared that β-carotene and retinol significantly reduced B[a]P-induced mutagenicity and oxidative stress. Tested carotenoids and retinoids reduced B[a]P-induced phase I XMEs and induced B[a]P reduced phase II and III XMEs. Thus, the protective effects of these micronutrients are probably due to their ability of induction of phase II and III enzymes and interference with the induction of phase I enzymes by the promutagen, B[a]P. It is highly recommended to consume foods rich in these micronutrients in the areas of high PAH pollution.

Twenty Angus steers were fed a diet low in β-carotene and vitamin A for 10months. Ten steers were supplemented with vitamin A weekly, while the other ten steers did not receive any additional vitamin A. The results demonstrated that the restriction of vitamin A intake increased intramuscular fat (IMF) by 46%. This was a function of the total number of marbling flecks increasing by 22% and the average marbling fleck size increasing by 14%. Vitamin A restriction resulted in marbling flecks that were less branched (22%) and slightly more round (4%) with an increased minor axis length (7%). However, restricting vitamin A did not affect the size of the intramuscular or subcutaneous adipocyte cells or the subcutaneous fat depth. The results suggest that vitamin A affects the amount of marbling and other attributes of the marbling flecks due to hyperplasia rather than hypertrophy. This may explain why vitamin A restriction specifically affects IMF rather than subcutaneous fat deposition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Vitamin A is an essential micronutrient for life and the phytochemical β-carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator.

Background: Provitamin A carotenoids are an important source of dietary vitamin A for many populations. Thus, accurate and simple methods for estimating carotenoid bioefficacy are needed to evaluate the vitamin A value of test solutions and plant sources. β-Carotene bioefficacy is often estimated from the ratio of the areas under plasma isotope response curves after subjects ingest labeled β-carotene and a labeled retinyl acetate reference dose [isotope reference method (IRM)], but to our knowledge, the method has not yet been evaluated for accuracy. Objectives: Our objectives were to develop and test a physiologically based compartmental model that includes both absorptive and postabsorptive β-carotene bioconversion and to use the model to evaluate the accuracy of the IRM and a simple plasma retinol isotope ratio [(RIR), labeled β-carotene-derived retinol/labeled reference-dose-derived retinol in one plasma sample] for estimating relative bioefficacy. Methods: We used model-based compartmental analysis (Simulation, Analysis and Modeling software) to develop and apply a model that provided known values for β-carotene bioefficacy. Theoretical data for 10 subjects were generated by the model and used to determine bioefficacy by RIR and IRM; predictions were compared with known values. We also applied RIR and IRM to previously published data. Results: Plasma RIR accurately predicted β-carotene relative bioefficacy at 14 d or later. IRM also accurately predicted bioefficacy by 14 d, except that, when there was substantial postabsorptive bioconversion, IRM underestimated bioefficacy. Based on our model, 1-d predictions of relative bioefficacy include absorptive plus a portion of early postabsorptive conversion. Conclusion: The plasma RIR is a simple tracer method that accurately predicts β-carotene relative bioefficacy based on analysis of one blood sample obtained at ≥14 d after co-ingestion of labeled β-carotene and retinyl acetate. The method also provides information about the contributions of absorptive and postabsorptive conversion to total bioefficacy if an additional sample is taken at 1 d., Competing Interests: Author disclosures: JLF, JBG, GL, AO, and MHG, no conflicts of interest., (© 2017 American Society for Nutrition.)

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Vitamin A and its metabolites (called retinoids) have been thought to play a role in the development of idiopathic intracranial hypertension (IIH). The IIH Treatment Trial (IIHTT) showed the efficacy of acetazolamide (ACZ) in improving visual field function, papilledema grade, quality of life and cerebrospinal fluid (CSF) pressure. We postulated that IIH patients would demonstrate elevated measures of vitamin A metabolites in the serum and CSF., Methods: Comprehensive measures of serum vitamin A and its metabolites were obtained from 96 IIHTT subjects, randomly assigned to treatment with ACZ or placebo, and 25 controls with similar gender, age and body mass index (BMI). These included retinol, retinol binding protein, all-trans retinoic acid (ATRA), alpha- and beta-carotenes, and beta-cryptoxanthin. The IIHTT subjects also had CSF and serum vitamin A and metabolite measurements obtained at study entry and at six months., Results: At study entry, of the vitamin A metabolites only serum ATRA was significantly different in IIHTT subjects (median 4.33nM) and controls (median 5.04nM, p=0.02). The BMI of IIHTT subjects showed mild significant negative correlations with serum ATRA, alpha- and beta-carotene, and beta-cryptoxanthin. In contrast, the control subject BMI correlated only with serum ATRA. At six months, the serum retinol, alpha-carotene, beta-carotene, and CSF retinol were increased from baseline in the ACZ treated group, but only increases in alpha-carotene (p=0.02) and CSF ATRA (p=0.04) were significantly greater in the ACZ group compared with the placebo group. No other vitamin A measures were significantly altered over the six months in either treatment group. Weight loss correlated with only with the change in serum beta-carotene (r=-0.44, p=0.006) and the change in CSF retinol (r=-0.61, p=0.02)., Conclusion: Vitamin A toxicity is unlikely a contributory factor in the causation of IIH. Our findings differ from those of prior reports in part because of our use of more accurate quantitative methods and measuring vitamin A metabolites in both serum and CSF. ACZ may alter retinoid metabolism in IIH patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)