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Nutrients Mar 2017Blood concentration of vitamin A (VA), which is present as different molecules, i.e., mainly retinol and provitamin A carotenoids, plus retinyl esters in the... (Review)
Review
Blood concentration of vitamin A (VA), which is present as different molecules, i.e., mainly retinol and provitamin A carotenoids, plus retinyl esters in the postprandial period after a VA-containing meal, is affected by numerous factors: dietary VA intake, VA absorption efficiency, efficiency of provitamin A carotenoid conversion to VA, VA tissue uptake, etc. Most of these factors are in turn modulated by genetic variations in genes encoding proteins involved in VA metabolism. Genome-wide association studies (GWAS) and candidate gene association studies have identified single nucleotide polymorphisms (SNPs) associated with blood concentrations of retinol and β-carotene, as well as with β-carotene bioavailability. These genetic variations likely explain, at least in part, interindividual variability in VA status and in VA bioavailability. However, much work remains to be done to identify all of the SNPs involved in VA status and bioavailability and to assess the possible involvement of other kinds of genetic variations, e.g., copy number variants and insertions/deletions, in these phenotypes. Yet, the potential usefulness of this area of research is exciting regarding the proposition of more personalized dietary recommendations in VA, particularly in populations at risk of VA deficiency.
Topics: Biological Availability; DNA Copy Number Variations; Diet; Gastrointestinal Absorption; Genetic Association Studies; Humans; Liver; Polymorphism, Single Nucleotide; Postprandial Period; Recommended Dietary Allowances; Vitamin A; Vitamin A Deficiency
PubMed: 28282870
DOI: 10.3390/nu9030246 -
Methods in Enzymology 2020Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from...
Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol binding-protein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin: retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes.
Topics: Animals; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin; Vitamin A
PubMed: 32359649
DOI: 10.1016/bs.mie.2020.02.003 -
Advances in Experimental Medicine and... 2023Mucormycosis is a rare but serious opportunistic fungal disease characterized by rhino-orbito-cerebral and pulmonary involvement. It is mainly seen in people with...
Mucormycosis is a rare but serious opportunistic fungal disease characterized by rhino-orbito-cerebral and pulmonary involvement. It is mainly seen in people with secondary immunosuppression, isolated vitamin A deficiency, measles, and AIDS patients. It showed a rise during the second wave of the COVID-19 epidemic in the spring of 2021 in India, especially in diabetic COVID-19 patients. Vitamin A deficiency is known to cause nutritional immunodeficiency and hence leading the way to increased opportunistic fungal, bacterial, and viral infections. In the eye, it causes keratitis, night blindness, xerophthalmia, conjunctivitis, Bitot spots, keratomalacia, and retinopathy. It also causes decreased tear secretion and deterioration of the anatomical/physiological defense barrier of the eye. The negative impact of vitamin A deficiency has been previously demonstrated in measles, AIDS, and COVID-19. We think that mucormycosis in COVID-19 might be rendered by vitamin A deficiency and that vitamin A supplementation may have preventive and therapeutic values against mucormycosis and other ocular symptoms associated with COVID-19. However, any vitamin A treatment regimen needs to be based on laboratory and clinical data and supervised by medical professionals.
Topics: Humans; Mucormycosis; Vitamin A Deficiency; Vitamin A; Acquired Immunodeficiency Syndrome; COVID-19; Eye Diseases; Fungi
PubMed: 37253944
DOI: 10.1007/5584_2023_774 -
Journal of Molecular Endocrinology Nov 2022The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid... (Review)
Review
The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid receptors. This stunning breakthrough triggered a cascade of studies to deconstruct the roles played by the RAR and its natural and synthetic ligands in embryonic development, skin, growth, physiology, vision, and disease as well as providing a template to elucidate the molecular mechanisms by which nuclear receptors regulate gene expression. In this review, written from historic and personal perspectives, we highlight the milestones that led to the discovery of the RAR and the subsequent studies that enriched our knowledge of the molecular mechanisms by which a low-abundant dietary compound could be so essential to the generation and maintenance of life itself.
Topics: Ligands; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Tretinoin; Vitamin A
PubMed: 35900848
DOI: 10.1530/JME-22-0117 -
Nutrients Mar 2022Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the... (Review)
Review
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.
Topics: Feedback; Lipid Metabolism; Retinoids; Tretinoin; Vitamin A
PubMed: 35334970
DOI: 10.3390/nu14061312 -
Wiley Interdisciplinary Reviews.... May 2017Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and... (Review)
Review
Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and retinoic acid can cause similar developmental defects. Therefore, strict feedback and other mechanisms exist to regulate the levels of retinoic acid within a narrow physiological range. The oxidation of vitamin A to retinal has recently been established as a critical nodal point in the synthesis of retinoic acid, and over the past decade, RDH10 and DHRS3 have emerged as the predominant enzymes that regulate this reversible reaction. Together they form a codependent complex that facilitates negative feedback maintenance of retinoic acid levels and thus guard against the effects of dysregulated vitamin A metabolism and retinoic acid synthesis. This review focuses on advances in our understanding of the roles of Rdh10 and Dhrs3 and their impact on development and disease. WIREs Dev Biol 2017, 6:e264. doi: 10.1002/wdev.264 For further resources related to this article, please visit the WIREs website.
Topics: Animals; Embryonic Development; Homeostasis; Humans; Signal Transduction; Vitamin A
PubMed: 28207193
DOI: 10.1002/wdev.264 -
Vitamin A and inflammatory bowel diseases: from cellular studies and animal models to human disease.Expert Review of Gastroenterology &... Jan 2019Vitamin A (VA) and metabolites such as Retinoic Acid (RA) and all-trans-RA (at-RA) are crucial in the modulation of the immune system and may be determinative in the... (Review)
Review
Vitamin A (VA) and metabolites such as Retinoic Acid (RA) and all-trans-RA (at-RA) are crucial in the modulation of the immune system and may be determinative in the balance of the immune responses. Inflammatory bowel diseases (IBD) consist of chronic relapsing and heterogeneous disorders with not well-known etiology. Due to its role in inflammatory processes, VA may be helpful in the treatment of IBD. Area covered: As VA plays a significant role in the inflammatory processes, this review aims to show the potential role of this vitamin in IBD, searching for cellular studies, animal models, and studies with humans. Expert commentary: Many studies have described the importance of alternative therapeutic approaches for IBD. Due to its role in the immune system, VA may also exert an indispensable role in the IBD. Nevertheless, some authors have shown that these compounds could stimulate the release of pro-inflammatory cytokines. For these reasons, more studies should be performed to establish the precise mechanisms of VA and its metabolites in systemic and intestinal inflammation.
Topics: Animals; Anti-Inflammatory Agents; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Risk Factors; Treatment Outcome; Vitamin A
PubMed: 30791845
DOI: 10.1080/17474124.2019.1543588 -
Journal of Lipid Research 2021Lecithin:retinol acyltransferase and retinol-binding protein enable vitamin A (VA) storage and transport, respectively, maintaining tissue homeostasis of retinoids (VA...
Lecithin:retinol acyltransferase and retinol-binding protein enable vitamin A (VA) storage and transport, respectively, maintaining tissue homeostasis of retinoids (VA derivatives). The precarious VA status of the lecithin:retinol acyltransferase-deficient (Lrat) retinol-binding protein-deficient (Rbp) mice rapidly deteriorates upon dietary VA restriction, leading to signs of severe vitamin A deficiency (VAD). As retinoids impact gut morphology and functions, VAD is often linked to intestinal pathological conditions and microbial dysbiosis. Thus, we investigated the contribution of VA storage and transport to intestinal retinoid homeostasis and functionalities. We showed the occurrence of intestinal VAD in LratRbp mice, demonstrating the critical role of both pathways in preserving gut retinoid homeostasis. Moreover, in the mutant colon, VAD resulted in a compromised intestinal barrier as manifested by reduced mucins and antimicrobial defense, leaky gut, increased inflammation and oxidative stress, and altered mucosal immunocytokine profiles. These perturbations were accompanied by fecal dysbiosis, revealing that the VA status (sufficient vs. deficient), rather than the amount of dietary VA per se, is likely a major initial discriminant of the intestinal microbiome. Our data also pointed to a specific fecal taxonomic profile and distinct microbial functionalities associated with VAD. Overall, our findings revealed the suitability of the LratRbp mice as a model to study intestinal dysfunctions and dysbiosis promoted by changes in tissue retinoid homeostasis induced by the host VA status and/or intake.
Topics: Vitamin A
PubMed: 33587919
DOI: 10.1016/j.jlr.2021.100046 -
Nutrients Mar 2022Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ,... (Review)
Review
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.
Topics: Humans; Liver Diseases; Receptors, Retinoic Acid; Retinoids; Tretinoin; Vitamin A
PubMed: 35406069
DOI: 10.3390/nu14071456 -
Frontiers in Immunology 2019Vitamin A deficiencies and insufficiencies are widespread in developing countries, and may be gaining prevalence in industrialized nations. To combat vitamin A...
Vitamin A deficiencies and insufficiencies are widespread in developing countries, and may be gaining prevalence in industrialized nations. To combat vitamin A deficiency (VAD), the World Health Organization (WHO) recommends high-dose vitamin A supplementation (VAS) in children 6-59 months of age in locations where VAD is endemic. This practice has significantly reduced all-cause death and diarrhea-related mortalities in children, and may have in some cases improved immune responses toward pediatric vaccines. However, VAS studies have yielded conflicting results, perhaps due to influences of baseline vitamin A levels on VAS efficacy, and due to cross-regulation between vitamin A and related nuclear hormones. Here we provide a brief review of previous pre-clinical and clinical data, showing how VAD and VAS affect immune responses, vaccines, and infectious diseases. We additionally present new results from a VAD mouse model. We found that when VAS was administered to VAD mice at the time of vaccination with a pneumococcal vaccine (Prevnar-13), pneumococcus (T4)-specific antibodies were significantly improved. Preliminary data further showed that after challenge with , all mice that had received VAS at the time of vaccination survived. This was a significant improvement compared to vaccination without VAS. Data encourage renewed attention to vitamin A levels, both in developed and developing countries, to assist interpretation of data from vaccine research and to improve the success of vaccine programs.
Topics: Animals; Dietary Supplements; Female; Immunogenicity, Vaccine; Male; Mice; Mice, Inbred C57BL; Pneumococcal Vaccines; Pregnancy; Vaccination; Vitamin A; Vitamin A Deficiency
PubMed: 31379816
DOI: 10.3389/fimmu.2019.01576