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Nutrients Apr 2022The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells,... (Review)
Review
The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Here, we discuss the potential link between the roles played by RA in shaping intestinal immune responses and the manifestations and pathogenesis of HIV-associated enteropathy and similar conditions observed in SIV-infected non-human primate models. We also present data demonstrating the ability of RA to enhance the activation of replication-competent viral reservoirs from subjects on suppressive anti-retroviral therapy. The data suggest that retinoid supplementation may be a useful adjuvant for countering the pathologic condition of the gastro-intestinal tract associated with HIV infection and as part of a strategy for reactivating viral reservoirs as a means of depleting latent viral infection.
Topics: Animals; HIV Infections; Humans; Immunity, Mucosal; Tretinoin; Virus Replication; Vitamin A
PubMed: 35458172
DOI: 10.3390/nu14081611 -
Translational Psychiatry Feb 2023The small, hormone-like molecule retinoic acid (RA) is a vital regulator in several neurobiological processes that are affected in depression. Next to its involvement in...
The small, hormone-like molecule retinoic acid (RA) is a vital regulator in several neurobiological processes that are affected in depression. Next to its involvement in dopaminergic signal transduction, neuroinflammation, and neuroendocrine regulation, recent studies highlight the role of RA in homeostatic synaptic plasticity and its link to neuropsychiatric disorders. Furthermore, experimental studies and epidemiological evidence point to the dysregulation of retinoid homeostasis in depression. Based on this evidence, the present study investigated the putative link between retinoid homeostasis and depression in a cohort of 109 patients with major depressive disorder (MDD) and healthy controls. Retinoid homeostasis was defined by several parameters. Serum concentrations of the biologically most active Vitamin A metabolite, all-trans RA (at-RA), and its precursor retinol (ROL) were quantified and the individual in vitro at-RA synthesis and degradation activity was assessed in microsomes of peripheral blood-derived mononuclear cells (PBMC). Additionally, the mRNA expression of enzymes relevant to retinoid signaling, transport, and metabolism were assessed. Patients with MDD had significantly higher ROL serum levels and greater at-RA synthesis activity than healthy controls providing evidence of altered retinoid homeostasis in MDD. Furthermore, MDD-associated alterations in retinoid homeostasis differed between men and women. This study is the first to investigate peripheral retinoid homeostasis in a well-matched cohort of MDD patients and healthy controls, complementing a wealth of preclinical and epidemiological findings that point to a central role of the retinoid system in depression.
Topics: Male; Humans; Female; Retinoids; Depressive Disorder, Major; Leukocytes, Mononuclear; Tretinoin; Vitamin A; Homeostasis
PubMed: 36813763
DOI: 10.1038/s41398-023-02362-0 -
Journal of Lipid Research Oct 2022Hepatocytes secrete retinol-binding protein 4 (RBP4) into circulation, thereby mobilizing vitamin A from the liver to provide retinol for extrahepatic tissues. Obesity...
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.
Topics: Mice; Animals; Vitamin A; Liver; Insulin; Tretinoin; Glucose
PubMed: 36030930
DOI: 10.1016/j.jlr.2022.100268 -
Nutrients Mar 2022Vitamin A is vital to maternal-fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and...
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 ( = 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--retinoic acid (-34%), and albumin (-22%) concentrations were significantly lower, and -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--retinoic acid (-23%) and 4-oxo-13--retinoic acid (-48%) concentrations were significantly lower, whereas plasma -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 -retinoic acid concentrations are higher than postpartum.
Topics: Female; Humans; Prealbumin; Pregnancy; Pregnant Women; Retinoids; Retinol-Binding Proteins, Plasma; Tretinoin; Vitamin A
PubMed: 35405978
DOI: 10.3390/nu14071365 -
International Journal of Toxicology 2017
Topics: Consumer Product Safety; Cosmetics; Diterpenes; Humans; Retinyl Esters; Risk Assessment; Skin Absorption; Ultraviolet Rays; Vitamin A
PubMed: 29025343
DOI: 10.1177/1091581817716657 -
Advances in Nutrition (Bethesda, Md.) May 2020Vitamin A is a fat-soluble essential nutrient obtained from plant- and animal-based sources that has roles in growth, vision, and metabolism. Vitamin A circulates mainly... (Review)
Review
Retinol, Retinoic Acid, and Retinol-Binding Protein 4 are Differentially Associated with Cardiovascular Disease, Type 2 Diabetes, and Obesity: An Overview of Human Studies.
Vitamin A is a fat-soluble essential nutrient obtained from plant- and animal-based sources that has roles in growth, vision, and metabolism. Vitamin A circulates mainly as retinol bound to retinol-binding protein 4 (RBP4), and is delivered to tissues and converted to retinoic acid, which is a ligand for several nuclear receptors. In recent years, aspects of vitamin A metabolism have been under scrutiny with regards to the development of metabolic and lifestyle diseases including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and overweight and obesity in humans. Studies have mainly focused on RBP4 in this context, whereas the major circulating form, retinol, and the major bioactive form, retinoic acid, have been overlooked in this regard until recently. As one of the main roles of RBP4 is to deliver retinol to tissues for biological action, the associations of retinol and retinoic acid with these diseases must also be considered. In this review, we summarize and discuss recent and available evidence from human studies with focus on retinol, retinoic acid, and RBP4 and provide an overview of these crucial components of vitamin A metabolism in CVD, T2DM, and obesity. In summary, retinol was found to be both inversely and positively associated with CVD whereas the associations with T2DM and obesity were less clear. Although only a few studies have been published on retinoic acid, it was inversely associated with CVD. In contrast, serum RBP4 was mostly found to be positively associated with CVD, T2DM, and obesity. At present, it is difficult to ascertain why the reported associations differ depending on the compound under study, but there is a clear imbalance in the literature in disfavor of retinol and retinoic acid, which needs to be considered in future human studies.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Obesity; Retinol-Binding Proteins, Plasma; Tretinoin; Vitamin A
PubMed: 31868199
DOI: 10.1093/advances/nmz131 -
Nutrients Apr 2022Cellular retinoic acid binding proteins (CRABP1 and CRABP2) bind -retinoic acid (RA), the active metabolite of vitamin A, with high affinity. CRABP1 and CRABP2 have been...
Cellular retinoic acid binding proteins (CRABP1 and CRABP2) bind -retinoic acid (RA), the active metabolite of vitamin A, with high affinity. CRABP1 and CRABP2 have been shown to interact with the RA-clearing cytochrome P450 enzymes CYP26B1 and CYP26C1 and with nuclear retinoic acid receptors (RARs). We hypothesized that CRABP1 and CRABP2 also alter RA metabolism and clearance by CYP26A1, the third key RA-metabolizing enzyme in the CYP26 family. Based on stopped-flow experiments, RA bound CRABP1 and CRABP2 with K values of 4.7 nM and 7.6 nM, respectively. The unbound RA K values for 4-OH-RA formation by CYP26A1 were 4.7 ± 0.8 nM with RA, 6.8 ± 1.7 nM with holo-CRABP1 and 6.1 ± 2.7 nM with holo-CRABP2 as a substrate. In comparison, the apparent k value was about 30% lower (0.71 ± 0.07 min for holo-CRABP1 and 0.75 ± 0.09 min for holo-CRABP2) in the presence of CRABPs than with free RA (1.07 ± 0.08 min). In addition, increasing concentrations in apo-CRABPs decreased the 4-OH-RA formation rates by CYP26A1. Kinetic analyses suggest that apo-CRABP1 and apo-CRABP2 inhibit CYP26A1 (K = 0.39 nM and 0.53 nM, respectively) and holo-CRABPs channel RA for metabolism by CYP26A1. These data suggest that CRABPs play a critical role in modulating RA metabolism and cellular RA concentrations.
Topics: Cytochrome P-450 Enzyme System; Retinoic Acid 4-Hydroxylase; Retinol-Binding Proteins; Tretinoin; Vitamin A
PubMed: 35565751
DOI: 10.3390/nu14091784 -
Journal of Molecular Endocrinology Nov 2022Vitamin A (retinol) is an important nutrient for embryonic development and adult health. Early studies identified retinoic acid (RA) as a metabolite of retinol, however,...
Vitamin A (retinol) is an important nutrient for embryonic development and adult health. Early studies identified retinoic acid (RA) as a metabolite of retinol, however, its importance was not apparent. Later, it was observed that RA treatment of vertebrate embryos had teratogenic effects on limb development. Subsequently, the discovery of nuclear RA receptors (RARs) revealed that RA controls gene expression directly at the transcriptional level through a process referred to as RA signaling. This important discovery led to further studies demonstrating that RA and RARs are required for normal embryonic development. The determination of RA function during normal development has been challenging as RA gain-of-function studies often lead to conclusions about normal development that conflict with RAR or RA loss-of-function studies. However, genetic loss-of-function studies have identified direct target genes of endogenous RA/RAR that are required for normal development of specific tissues. Thus, genetic loss-of-function studies that eliminate RARs or RA-generating enzymes have been instrumental in revealing that RA signaling is required for normal early development of many organs and tissues, including the hindbrain, posterior body axis, somites, spinal cord, forelimbs, heart, and eye.
Topics: Animals; Carrier Proteins; Female; Pregnancy; Receptors, Retinoic Acid; Signal Transduction; Tretinoin; Vitamin A
PubMed: 35593389
DOI: 10.1530/JME-22-0041 -
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 -
Proceedings of the National Academy of... Nov 2022For sustained vision, photoactivated rhodopsin (Rho*) must undergo hydrolysis and release of all--retinal, producing substrate for the visual cycle and apo-opsin...
For sustained vision, photoactivated rhodopsin (Rho*) must undergo hydrolysis and release of all--retinal, producing substrate for the visual cycle and apo-opsin available for regeneration with 11--retinal. The kinetics of this hydrolysis has yet to be described for rhodopsin in its native membrane environment. We developed a method consisting of simultaneous denaturation and chromophore trapping by isopropanol/borohydride, followed by exhaustive protein digestion, complete extraction, and liquid chromatography-mass spectrometry. Using our method, we tracked Rho* hydrolysis, the subsequent formation of -retinylidene-phosphatidylethanolamine (-ret-PE) adducts with the released all--retinal, and the reduction of all--retinal to all--retinol. We found that hydrolysis occurred faster in native membranes than in detergent micelles typically used to study membrane proteins. The activation energy of the hydrolysis in native membranes was determined to be 17.7 ± 2.4 kcal/mol. Our data support the interpretation that metarhodopsin II, the signaling state of rhodopsin, is the primary species undergoing hydrolysis and release of its all--retinal. In the absence of NADPH, free all--retinal reacts with phosphatidylethanolamine (PE), forming a substantial amount of -ret-PE (∼40% of total all--retinal at physiological pH), at a rate that is an order of magnitude faster than Rho* hydrolysis. However, -ret-PE formation was highly attenuated by NADPH-dependent reduction of all--retinal to all--retinol. Neither -ret-PE formation nor all--retinal reduction affected the rate of hydrolysis of Rho*. Our study provides a comprehensive picture of the hydrolysis of Rho* and the release of all--retinal and its reentry into the visual cycle, a process in which alteration can lead to severe retinopathies.
Topics: Rhodopsin; Retinaldehyde; Vitamin A; Hydrolysis; NADP
PubMed: 36322748
DOI: 10.1073/pnas.2213911119