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International Journal of Molecular... May 2023Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we...
Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis was observed in vitamin A-deficient (VAD) mice than in vitamin A-sufficient (VAS) mice; the same was observed in VAD severe combined immunodeficient mice lacking T/B cells. Remarkably, IL-1β production, LC3B-II expression, and inflammasome activity in the lamina propria were significantly elevated in VAD mice. Electron microscopy revealed numerous swollen mitochondria with severely disrupted cristae. In vitro, non-canonical inflammasome signaling-induced pyroptosis, LC3B-II and p62 expression, and mitochondrial superoxide levels were increased in murine macrophages (RAW 264.7) pretreated with retinoic acid receptor antagonist (Ro41-5253). These findings suggest that vitamin A plays a crucial role in the efficient fusion of autophagosomes with lysosomes in colitis.
Topics: Animals; Mice; Inflammasomes; Vitamin A; Dextran Sulfate; Colitis; Lysosomes; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37240022
DOI: 10.3390/ijms24108684 -
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 -
Global Health, Science and Practice Jun 2022To identify vitamin A supplementation (VAS) trends in South Sudan and provide insights to refocus VAS programming vis a vis polio eradication campaigns recently phased... (Review)
Review
AIM
To identify vitamin A supplementation (VAS) trends in South Sudan and provide insights to refocus VAS programming vis a vis polio eradication campaigns recently phased out while access to health care, land, food, and markets remain challenging.
METHOD
Review of data from survey and coverage reports; review of policy and program documents; key informant responses; general literature search.
RESULTS
Vitamin A deficiency (VAD) is likely a severe public health problem among preschool-aged children in South Sudan based on a high under-5 mortality rate (96.2 deaths/1,000 live births) and high levels of undernutrition, infections, and food insecurity. Vitamin A capsules, with deworming tablets (VASD), have been delivered to preschool-aged children during national immunization days (NIDs) for the past decade. Although areas of South Sudan and certain populations continue to have low VAS coverage, when comparing national VAS coverage (reported in the last 6 months) between 2010 and August 2019, a large improvement is noted from 4% to 76%. In 2021, VAS coverage was more than 90% at the national level during 2 stand-alone distribution campaigns. Deworming coverage trends generally mimicked VAS coverage. VAS is provided to postpartum mothers who deliver at health facilities (approximately 12%-25%), but coverage data are not available.
CONCLUSION
Twice-yearly VAS should remain a key lifesaving intervention to address VAD, but alternative delivery strategies will be needed. Conducting events, such as child health days, supported by promotional activities or community-based VASD distribution activities for the youngest children and those missed during campaigns, should be considered. For the long term, a hybrid approach targeting underserved areas with mass distribution events while integrating VASD into community-based programs such as quarterly screening for wasting should be tested further and gradually scaled up everywhere as this has the potential to sustainably reach all vulnerable children twice yearly.
Topics: Child, Preschool; Child; Female; Humans; Infant; Vitamin A; South Sudan; Vitamin A Deficiency; Mothers; Dietary Supplements
PubMed: 36332070
DOI: 10.9745/GHSP-D-21-00660 -
Clinical Nutrition (Edinburgh, Scotland) May 2021The prospective relation of dietary vitamin A intake with hypertension remains uncertain. We aimed to investigate the relationship of dietary vitamin A intake with...
BACKGROUND & AIMS
The prospective relation of dietary vitamin A intake with hypertension remains uncertain. We aimed to investigate the relationship of dietary vitamin A intake with new-onset hypertension and examine possible effect modifiers in general population.
METHODS
This prospective cohort study included 12,245 participants who were free of hypertension at baseline from China Health and Nutrition Survey (CHNS). Dietary intake was measured by 3 consecutive 24-h dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or diagnosed by physician or under antihypertensive treatment during the follow-up.
RESULTS
During a median follow-up duration of 6.1 years, a total of 4,304 (35.1%) participants developed new-onset hypertension. Overall, there was an L-shaped relation of total dietary vitamin A intake with new-onset hypertension (P for nonlinearity <0.001). Accordingly, compared with participants with lower vitamin A intake (quartile 1, <227.3 μg RE/day), those with higher vitamin A intake (quartile 2-4, ≥227.3 μg RE/day) had a significantly lower risk of new-onset hypertension (adjusted HR, 0.73; 95%CI: 0.63, 0.78). Similar results were found for plant-derived vitamin A intake (adjusted HR, 0.65; 95% CI, 0.61, 0.70) or animal-derived vitamin A intake (adjusted HR, 0.76; 95% CI, 0.70, 0.82).
CONCLUSIONS
There was a L-shaped relation of dietary vitamin A intake with new-onset hypertension in general Chinese adults. Our results emphasized the importance of maintaining relatively higher vitamin A intake levels for the prevention of hypertension.
Topics: Adult; Antihypertensive Agents; Cohort Studies; Diet; Female; Humans; Hypertension; Male; Prospective Studies; Vitamin A
PubMed: 33940400
DOI: 10.1016/j.clnu.2021.04.004 -
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 -
Mechanisms of Transport and Delivery of Vitamin A and Carotenoids to the Retinal Pigment Epithelium.Molecular Nutrition & Food Research Aug 2019Vision depends on the delivery of vitamin A (retinol) to the retina. Retinol in blood is bound to retinol-binding protein (RBP). Retinal pigment epithelia (RPE) cells... (Review)
Review
Vision depends on the delivery of vitamin A (retinol) to the retina. Retinol in blood is bound to retinol-binding protein (RBP). Retinal pigment epithelia (RPE) cells express the RBP receptor, STRA6, that facilitates uptake of retinol. The retinol is then converted to retinyl esters by the enzyme lecithin:retinol acyltransferase. The esters are the substrate for RPE65, an enzyme that produces 11-cis retinol, which is converted to 11-cis retinaldehyde for transport to the photoreceptors to form rhodopsin. The dietary xanthophylls, lutein (LUT) and zeaxanthin (ZEA), accumulate in the macula of the eye, providing protection against age-related macular degeneration. To reach the macula, carotenoids cross the RPE. In blood, xanthophylls and β-carotene mostly associate with high-density lipoprotein (HDL) and low-density lipoprotein (LDL), respectively. Studies using a human RPE cell model evaluate the kinetics of cell uptake when carotenoids are delivered in LDL or HDL. For LUT and β-carotene, LDL delivery result in the highest rate of uptake. HDL is more effective in delivering ZEA (and meso-ZEA). This selective HDL-mediated uptake of ZEA, via a scavenger receptor and LDL-mediated uptake of LUT and β-carotene provides a mechanism for the selective accumulation of ZEA > LUT and xanthophylls over β-carotene in the macula.
Topics: Animals; Carotenoids; Diet; Humans; Intestinal Absorption; Lipoproteins, HDL; Lipoproteins, LDL; Retinal Pigment Epithelium; Vitamin A
PubMed: 30698921
DOI: 10.1002/mnfr.201801046 -
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