Metabolism of retinoic acid in vivo in the vitamin A-deficient rat.
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ABSTRACT:
SUBMITTER: Silva DP
PROVIDER: S-EPMC1158546 | biostudies-other | 1982 Jul
REPOSITORIES: biostudies-other
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Project description:In vitamin B-12 (cobalamin) deficiency the metabolism of propionyl-CoA and methylmalonyl-CoA are inhibited secondarily to decreased L-methylmalonyl-CoA mutase activity. Production of acylcarnitines provides a mechanism for removing acyl groups and liberating CoA under conditions of impaired acyl-CoA utilization. Carnitine metabolism was studied in the vitamin B-12-deficient rat to define the relationship between alterations in acylcarnitine generation and the development of methylmalonic aciduria. Urinary excretion of methylmalonic acid was increased 200-fold in vitamin B-12-deficient rats as compared with controls. Urinary acylcarnitine excretion was increased in the vitamin B-12-deficient animals by 70%. This increase in urinary acylcarnitine excretion correlated with the degree of metabolic impairment as measured by the urinary methylmalonic acid elimination. Urinary propionylcarnitine excretion averaged 11 nmol/day in control rats and 120 nmol/day in the vitamin B-12-deficient group. The fraction of total carnitine present as short-chain acylcarnitines in the plasma and liver of vitamin B-12-deficient rats was increased as compared with controls. When the rats were fasted for 48 h, relative or absolute increases were seen in the urine, plasma, liver and skeletal-muscle acylcarnitine content of the vitamin B-12-deficient rats as compared with controls. Thus vitamin B-12 deficiency was associated with a redistribution of carnitine towards acylcarnitines. Propionylcarnitine was a significant constituent of the acylcarnitine pool in the vitamin B-12-deficient animals. The changes in carnitine metabolism were consistent with the changes in CoA metabolism known to occur with vitamin B-12 deficiency. The vitamin B-12-deficient rat provides a model system for studying carnitine metabolism in the methylmalonic acidurias.
| S-EPMC1135203 | biostudies-other
Project description:1. Metabolism of folate was studied in six ewes in an advanced state of vitamin B(12) deficiency as judged by voluntary food intake and in their pair-fed controls receiving vitamin B(12). A group of four animals that were maintained throughout the experiment at pasture was also studied. 2. After 34-40 weeks on the cobalt-deficient diet urinary excretion of formiminoglutamate by four deficient animals was about 3.2mmol/day and this was not significantly decreased by injection of three of them with about 4.5mug of [2-(14)C]folate/kg body weight per day for 5 days. Three days after the last injection retention of [2-(14)C]folate by the livers of the deficient animals (5.5% of the dose) was lower than that of their pair-fed controls (26% of the dose) but there was no evidence of net retention of injected folate in the livers of either group. Urinary excretion of (14)C indicated that renal clearance of folate may have been impaired in very severe vitamin B(12) deficiency. 3. As estimated by microbiological assays total folates in the livers of animals at pasture (12.9mug/g) included about 24% of 5-methyltetrahydrofolate as compared with about 72% of a total of 12.5mug/g in three further ewes fed on a stock diet of wheaten hay-chaff and lucerne-chaff. Liver folates of vitamin B(12)-deficient animals (0.5mug/g) included about 88% of 5-methyltetrahydrofolate as compared with about 51% of a total of 5.2mug/g in pair-fed animals treated with vitamin B(12). 4. Chromatography of liver folates of the pair-fed animals permitted quantitative estimates of the pteroylglutamates present. The results showed that the vitamin B(12)-deficient livers were more severely depleted of tetrahydrofolates and formyltetrahydrofolates than of methyltetrahydrofolates and that as the deficiency developed they were more severely depleted of the higher polyglutamates than of the monoglutamate within each of these classes. Results from animals injected with [2-(14)C]folate indicated an impairment of the exchange between pteroylmonoglutamates and pteroylpolyglutamates in the livers of deficient animals. 5. In vitamin B(12)-deficient animals with food intakes below 200g/day some of the liver folates were not completely reduced and some degradation of pteroylpolyglutamates was detected. The latter condition may have been associated with fatty liver. 6. The results are discussed in relation to current theories of vitamin B(12)-folate interactions.
| S-EPMC1165953 | biostudies-other
Project description:Tryptophan contents of liver, serum and kidney were determined in normal and vitamin-B-6-deficient rats after tryptophan injection. Tryptophan contents of normal and B-6-deficient liver were different, but not those in serum and kidney. Both kynurenine and 3-hydroxykynurenine accumulated in B-6-deficient liver more than in the normal. The 3-hydroxykynurenine contents after tryptophan injection (30 mg/100 g body wt.) increased to 1380 nmol/g of liver at 1-1.5 h, a value sufficient to produce xanthurenate, in view of the Km value of kynurenine aminotransferase. The enzymes metabolizing kynurenine were assayed at various times after tryptophan injection. The activity of kynureninase holoenzyme in B-6-deficient liver was much decreased, but the activity of total enzyme was not changed. It appeared that a high dose of tryptophan in B-6-deficient rats could cause a greater deficiency of pyridoxal 5-phosphate. Tryptophan metabolism in B-6-deficient rat liver after tryptophan administration is discussed.
| S-EPMC1153685 | biostudies-other
Project description:1. The metabolism of retinoic acid and retinyl acetate labelled with (14)C in various positions was studied after intravenous injection of physiological amounts of these compounds into retinol-deficient rats. 2. Analysis of the resultant radio-activity in the urine, carbon dioxide and faeces led to a postulation of the existence of three major pathways for the metabolism of these two compounds. 3. Evidence is presented that retinoic acid and retinol are metabolized by either the same or at least similar pathways and that retinol becomes oxidized to the carboxyl state before any degradation of the isoprenoid side chain occurs. 4. It is not possible to decide from these data whether retinoic acid is an intermediate in the retinol pathway. 5. Possible sites for the regulation of retinol metabolism are discussed.
| S-EPMC1270285 | biostudies-other
Project description:An endogenous time-keeping mechanism controls circadian biological rhythms in mammals. Previously, we showed that vitamin A deficiency modifies clock BMAL1 and PER1 as well as BDNF and neurogranin daily rhythmicity in the rat hippocampus when animals are maintained under 12-h-light:12-h-dark conditions. Retinoic acid nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been detected in the same brain area. Our objectives were (a) to analyze whether RAR?, RAR? and RXR? exhibit a circadian variation in the rat hippocampus and (b) to investigate the effect of a vitamin-A-deficient diet on the circadian expression of BMAL1, PER1 and retinoic acid receptors (RARs and RXR?) genes. Holtzman male rats from control and vitamin-A-deficient groups were maintained under 12-h-light:12-h-dark or 12-h-dark:12-h-dark conditions during the last week of treatment. RAR?, RAR?, RXR?, BMAL1 and PER1 transcript and protein levels were determined in hippocampus samples isolated every 4 h in a 24-h period. Regulatory regions of RARs and RXR? genes were scanned for clock-responsive sites, while BMAL1 and PER1 promoters were analyzed for retinoic acid responsive elements and retinoid X responsive elements. E-box and retinoid-related orphan receptor responsive element sites were found on regulatory regions of retinoid receptors genes, which display an endogenously controlled circadian expression in the rat hippocampus. Those temporal profiles were modified when animals were fed with a vitamin-A-deficient diet. Similarly, the nutritional vitamin A deficiency phase shifted BMAL1 and abolished PER1 circadian expression at both mRNA and protein levels. Our data suggest that vitamin A deficiency may affect the circadian expression in the hippocampus by modifying the rhythmic profiles of retinoic acid receptors.
| S-EPMC3504648 | biostudies-literature
Project description:Vitamin A deficiency affects over 250 million preschool-age children worldwide and is associated with increased childhood mortality and risk of developing enteric infections. Vitamin A deficient (A-) mice developed chronic Citrobacter rodentium infection. A single oral dose of retinoic acid (RA) at d7 post-infection was sufficient to induce clearance of the pathogen in A- mice. RA treatment of A- mice induced il17 expression in the colon. In A- mice, colonic IL-17 was primarily produced by CD11b+ cells; however, in A+ mice, the major source of colonic IL-17 was CD4+ T cells. To determine the cellular targets of vitamin A required for host resistance to C. rodentium, mice that express a dominant negative (dn) retinoic acid receptor (RAR) in T cells (T-dnRAR) or macrophage/neutrophils (LysM-dnRAR) were used. T-dnRAR mice had T cells that produced a robust intestinal IL-17 response and for 40% of the mice was enough to clear the infection. The remainder of the T-dnRAR mice developed a chronic infection. A- LysM-dnRAR mice developed early lethal infections with surviving mice becoming chronically infected. RA treatment of A- LysM-dnRAR mice was ineffective for inducing colonic IL-17 or clearing C. rodentium. Retinoid signaling is required in T cells and CD11b+ cells for complete elimination of enteric pathogens.
| S-EPMC6331472 | biostudies-literature
Project description:Vitamin A deficiency (VAD) is a major public health problem and is associated with increased host susceptibility to infection; however, how VAD influences viral infection remains unclear. Using a persistent lymphocytic choriomeningitis virus infection model, we showed in this study that although VAD did not alter innate type I IFN production, infected VAD mice had hyperactive, virus-specific T cell responses at both the acute and contraction stages, showing significantly decreased PD-1 but increased cytokine (IFN-γ, TNF-α, and IL-2) expression by T cells. Compared with control mice, VAD mice displayed excessive inflammation and more severe liver pathology, with increased death during persistent infection. Of note, supplements of all-trans retinoic acid (RA), one of the important metabolites of vitamin A, downregulated hyperactive T cell responses and rescued the persistently infected VAD mice. By using adoptive transfer of splenocytes, we found that the environmental vitamin A or its metabolites acted as rheostats modulating antiviral T cells. The analyses of T cell transcriptional factors and signaling pathways revealed the possible mechanisms of RA, as its supplements inhibited the abundance of NFATc1 (NFAT 1), a key regulator for T cell activation. Also, following CD3/CD28 cross-linking stimulation, RA negatively regulated the TCR-proximal signaling in T cells, via decreased phosphorylation of Zap70 and its downstream signals, including phosphorylated AKT, p38, ERK, and S6, respectively. Together, our data reveal VAD-mediated alterations in antiviral T cell responses and highlight the potential utility of RA for modulating excessive immune responses and tissue injury in infectious diseases.
| S-EPMC7371257 | biostudies-literature
Project description:Vitamin A (VA), all-trans-retinol (at-ROL), and its derivative, all-trans-retinoic acid (at-RA), are required for neuron development. The effects of these retinoids are dependent upon the nutritional status of the rat and tissue-specific dynamics of retinoid access and utilization. The purpose of this study was to determine the status of at-ROL and at-RA in the peripheral olfactory organ of postnatal rats fed a normal diet and rats fed a VA-deficient (VAD) diet. Extracted retinoids were analyzed by HPLC. Resolved sample peaks were identified by comparing their elution times and spectra with those of authentic standards. Mean at-RA and at-ROL concentrations of 23 pmol/g olfactory tissue and 0.13 nmol/g, respectively, were recovered from olfactory tissue. The ratio of at-RA:at-ROL in olfactory was approximately 2 times that in testis and 200 times that in liver. at-ROL was depleted from the liver and olfactory organ of rats fed a VAD diet from birth to 70 d of age. Surprisingly, at-RA was still present in olfactory tissue from these rats. At 90 d of age, the VAD rats were frankly deficient and at-RA was no longer detectable in olfactory tissue. The comparatively high ratio of at-RA:at-ROL in the peripheral olfactory organ and the persistence of at-RA in at-ROL-depleted tissues strongly suggests that maintenance of local stores of at-RA is functionally relevant in this tissue.
| S-EPMC2682984 | biostudies-literature
Project description:Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improving dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate and supplemented), and acutely after administration of a therapeutic dose of all-trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P<0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding RARß, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log26 in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naïve rats. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling RBP4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.
2011-09-01 | GSE24104 | GEO
Project description:The transport of retinoic acid in plasma was examined in vitamin A-deficient rats maintained on small doses of radioactively labelled retinoic acid. After ultracentrifugation of serum adjusted to density 1.21, most of the radioactivity (83%) was associated with the proteins of density greater than 1.21, and not with the serum lipoproteins. Gel filtration of the labelled serum on Sephadex G-200 showed that the radioactive label was associated with protein in the molecular-weight range of serum albumin. On polyacrylamide-gel electrophoresis almost all of the recovered radioactivity migrated with serum albumin. Similar esults were obtained with serum from a normal control rat given a single oral dose of [(14)C]retinoic acid. These findings indicate that retinoic acid is transported in rat serum bound to serum albumin, and not by retinol-binding protein (the specific transport protein for plasma retinol). Several tissues and the entire remaining carcase of each rat were extracted with ethanol-acetone to determine the tissue distribution of retinoic acid and some of its metabolites. The total recover of radioactive compounds in in the entire body of the rat was about 7-9mug, representing less than 5% or 10% respectively of the total administered label in the two dosage groups studied. The results confirm that retinoic acid is not stored in any tissue. Most of the radioactive material was found in the carcase, rather than in the specific tissues analysed. Two-thirds of the radioactivity in the carcase appeared to represent unchanged retinoic acid. Of the tissues examined, the liver, kidneys and intestine had relatively high concentrations of radioactive compounds, whereas the testes and fat-pads had the lowest concentrations.
| S-EPMC1177657 | biostudies-other