Subcutaneous white adipose tissue-derived extracellular vesicle maintains intestinal homeostasis via IgA biosynthesis in aging mice
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ABSTRACT: To identify the potential iWAT-derived adipokines that regulate intestinal IgA biosynthesis, we conducted untargeted metabolomics in the serum of iFR and iSham mice. A total of 214 differential abundant metabolites were identified (log2FC >1 or <-1 and adjusted p-value <0.05) between the two groups. Pathway analysis showed that retinol metabolism was the most significantly altered pathway by iWAT removal. Despite retinol level remained unchanged, its downstream oxidized products, including retinal, RA, and all-trans-5,6-epoxy-RA, were significantly downregulated in the iFR mice. The reduction of RAs was further confirmed through using a targeted LC-MS/MS analysis.
INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase
PROVIDER: MTBLS12800 | MetaboLights | 2025-09-05
REPOSITORIES: MetaboLights
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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: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. All rats were housed in a room maintained at 22°C with a 12-h dark:light cycle, and food and water were freely available. For the Steady-State Vitamin A Study (experiment 1) and the Retinoic Acid 16-hour Kinetic Study (experiment 2), lactating female Sprague-Dawley rats with 12 female pups (purchased from Charles River Laboratories, Willmington, MA) were fed a vitamin A-deficient purified diet [AIN-93G diet, prepared by Research Diets, New Brunswick, NJ] to reduce the transfer of vitamin A in milk from mother to pups prior to the start of the study. For experiment 1, from weaning, the offspring were fed the same diet modified to contain vitamin A at one of four levels: 0 (vitamin A deficient), 0.4 mg retinol/kg diet (vitamin A marginal), 4 mg retinol/kg diet (vitamin A adequate control), or 100 mg retinol/kg diet (vitamin A supplemented). All rats were studied at 8 weeks of age. Rats were euthanized by carbon dioxide asphyxiation and blood and liver were collected rapidly and frozen in liquid nitrogen for storage at -80°C before analysis. In experiment 2, at 8 weeks of age female vitamin A-deficient rats were treated with ~100 ug of All-trans-Retinoic acid (at-RA) for 0 (vehicle only), 3, 6, 10 or 16 h (n=3-4/group). Tissues were collected and RNA was prepared in the same manner as in experiment 1. In the 90-minute "first pass" kinetic study (experiment 3), female rats were purchased at 6 weeks of age and fed a stock rodent diet. When the rats were 8 weeks old they were assigned to a control (naïve) group. Rats in the naive group received an equal amount of vehicle only (vegetable oil/5% ethanol). Food was removed immediately. Sixteen hours after priming, each rat was lightly anesthetized by isoflurane-oxygen inhalation and treated with ~25 ug all-trans-RA bound to albumin [10 ug RA per 100 g bo dy weight], injected into the exposed left common iliac vein. The incision was closed with a surgical staple. The rats were allowed to recover from the anesthesia. Rats were killed at 0 minute (vehicle injection), and 30, 60, and 90 min (n = 3/group) after injection of the RA test dose. Rats were euthanized by carbon dioxide asphyxiation and blood and liver were collected rapidly and frozen in liquid nitrogen for storage at -80°C before analysis. For experiment 1, five biological repeats were Vitamin A deficient, seven biological repeats were Vitamin A marginal, six biological repeats were Vitamin A adequate, and two biological repeats were Vitamin A supplemented. In experiment 2, three biological repeats were performed for each of the following treatments: untreated, at-RA for 3 hours, at-RA for 6 hours and at-RA for 16 hours. Four biological repeats were treated with at-RA for 10 hours. For experiment 3, two biological repeats were untreated and three biological repeats were performed for each of the following at-RA treatment times: 30, 60 and 90 minutes. A total of 47 samples were analyzed.
2011-08-31 | E-GEOD-24104 | biostudies-arrayexpress
Project description:The main active metabolite of Vitamin A, all-trans retinoic acid (RA), is responsible for proper cellular function and tissue organization. The role of RA has been extensively studied in development, but there is limited research on its role in the adult heart. Cellular retinol-binding protein, type 1 (CRBP1), encoded by retinol-binding protein, type 1 (Rbp1), regulates RA homeostasis by delivering vitamin A to enzymes for RA synthesis. An animal model of CRBP1 deficiency, such as Rbp1–/– mice, can provide insight into disrupted RA biosynthesis and signaling. In this work, a multi-omics approach was used to characterize the effect of CRBP1 loss. Retinoid homeostasis was disrupted in Rbp1-/- mouse heart tissue, as seen by a 33% and 24% decrease in RA levels in the left and right ventricles, respectively, compared to wild-type mice (WT). To further inform on the effect of disrupted RA homeostasis, we conducted high-throughput targeted metabolomics. A total of 222 metabolite and metabolite combinations were analyzed, with 33 having differential expression between Rbp1-/- and WT hearts. Additionally, we performed global proteome profiling to further characterize the impact of CRBP1 loss in adult mouse hearts. More than 2,606 unique proteins were identified, with 340 proteins having differential expression between Rbp1-/- and WT hearts. Pathway analysis performed on metabolomic and proteomic data revealed pathways related to cellular metabolism and cardiac metabolism were the most disrupted in Rbp1-/- mice. Together, these studies provide data for establishing the effect of dysregulated RA signaling in the adult mouse heart.
2022-10-13 | PXD029349 | Pride
Project description:Pigment regeneration is critical for the function of cone photoreceptors in bright and rapidly-changing light conditions. This process is facilitated by the recently-characterized retina visual cycle, in which Müller cells recycle spent all-trans-retinol visual chromophore back to 11-cis-retinol. This 11-cis-retinol is oxidized selectively in cones to the 11-cis-retinal used for pigment regeneration. However, the enzyme responsible for the oxidation of 11-cis-retinol remains unknown. Here, we sought to determine whether retinol dehydrogenase 10 (RDH10), upregulated in rod/cone hybrid retinas and expressed abundantly in Müller cells, is the enzyme that drives this reaction. We created mice lacking RDH10 either in cone photoreceptors, Müller cells, or the entire retina. In vivo electroretinography and transretinal recordings revealed normal cone photoresponses in all RDH10-deficient mouse lines. Notably, their cone-driven dark adaptation both in vivo and in isolated retina was unaffected, indicating that RDH10 is not required for the function of the retina visual cycle. We also generated transgenic mice expressing RDH10 ectopically in rod cells. However, rod dark adaptation was unaffected by the expression of RDH10 and transgenic rods were unable to use cis-retinol for pigment regeneration. We conclude that RDH10 is not the dominant retina 11-cis-RDH, leaving its primary function in the retina unknown.
2017-03-07 | GSE86442 | GEO
Project description:Embryonic stem cells (ESC) are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass in their developmental potential. ESCs pluripotency is maintained through a complex interplay of different signaling pathways and a network of transcription factors, which is centered around Oct3/4, Sox2 and Nanog. Although, in general, much is known about this pluripotency self-renewal circuitry, the molecular events that lead ESC to exit from pluripotency and begin differentiation are currently less known. Retinoic acid, an active metabolite of the vitamin A (retinol), plays important and pleiotropic roles in vertebrate embryonic development and ESC differentiation. Here we demonstrate that RA promotes early steps of ESC differentiation, and that ESC increase their capacity to synthesize RA during spontaneous differentiation as embryoid bodies, up-regulating the RA biosynthetic pathway components RDH1, RDH10, ADH3, RALDH2, and CRABP2. Microarray derived from total RNA of mESC not treated or treated with all-trans retinoic acid (ATRA) for 2 hours.
2016-02-10 | E-GEOD-66043 | biostudies-arrayexpress
Project description:Study of the effects of at-RA treatment on the transcriptome of murine Long-Term Hematopoietic Stem Cells (LT-HSCs) in the context of myocardial infarction (MI). MI was induced in female C57BL/6J mice aged 6 to approximately 12 weeks through permanent occlusion of the left anterior descending artery (LAD). Mice were intraperitoneally injected on the 1st and 2nd day after MI surgery with either 30 mg/kg body weight at-RA (Sigma-Aldrich; MI+at-RA condition), or with the corresponding amount of DMSO in phosphate-buffered saline (PBS) (MI+vehicle condition). Two days after MI, LT-HSCs (Lin-negative, Sca1-positive, c-Kit-positive, CD150-positive, CD48-negative, CD34-negative) were isolated from the bone marrow, sorted, and analyzed for their transcriptome profiles. This study aimed to understand how at-RA treatment influences gene expression in LT-HSCs following MI.
2025-02-06 | E-MTAB-13506 | biostudies-arrayexpress
Project description:Diabetic cardiomyopathy (DCM) is a primary myocardial injury induced by diabetes mellitus (DM) with a complex pathogenesis. In this study, we identified disordered cardiac retinol metabolism in T2DM mice and patients characterized by retinol (vitamin A, Rol) overload, all-trans retinoic acid (atRA) deficiency and retinoic acid receptors (RARs) reduction, and demonstrated that both cardiac Rol overload and atRA deficiency promote DCM by supplementing T2DM mice with Rol or atRA. Mechanically, by constructing cardiomyocyte-specific conditional RDH10-knockout mice and overexpressing RDH10 in T2DM mice via adeno-associated virus, we verified that the reduction in cardiac retinol dehydrogenase 10 (RDH10) is the initiating factor for cardiac retinol metabolism disorder and its resulting DCM. Additionally, lipotoxicity and ferroptosis contribute to the effect of retinol metabolism disorder on DCM. Based on these results, we suggest that the reduction of cardiac RDH10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying DCM.
2023-01-15 | GSE202418 | GEO
Project description:Microbiome Changes during the Trans-Antarctic Winter Traverse
| PRJEB9027 | ENA
Project description:Despite decades of pharmacological studies, how the ubiquitous cytoskeletal actin regulates synaptic transmission remains poorly understood. We addressed this issue with a tissue-specific knockout of actin β-isoform or γ-isoform, combined with recordings of postsynaptic EPSCs, presynaptic capacitance jumps or fluorescent synaptophysin-pHluorin changes, and electron microscopy in large calyx-type and small conventional hippocampal synapses. We found that actin restrains basal synaptic transmission during single action potential firings by lowering the readily releasable vesicle's release probability. Such an inhibition of basal synaptic transmission is turned into facilitation during repetitive firings by slowing down depletion of the readily releasable vesicle pool and, thus, short-term synaptic depression, leading to more effective synaptic transmission for a longer time. These mechanisms, together with the previous finding that actin promotes vesicle replenishment to the readily releasable pool, may control synaptic transmission and short-term synaptic plasticity at many synapses, contributing to neurological disorders caused by actin cytoskeleton impairment.
| S-EPMC11919605 | biostudies-literature
Project description:Type II conventional dendritic cells (cDC2) are functionally and phenotypically heterogenous. Previous work identified two major cDC2 subsets (cDC2A and cDC2B) and a transcriptionally related monocytic DC3 subset; however, the underlying microenvironmental cues governing their distinct differentiation pathways remain unclear. Here we delineate cDC2 lineage relationships, and the sequential signals required for cDC2A specification and maintenance. We show that T-bet+ cDC2A, arising from a Clec9a+ DC progenitor, express the retinol receptor RBPR2, require cell-intrinsic retinoic acid (RA) signaling for their maintenance in the spleen and mesenteric lymph nodes, and depend on intrinsic RA receptor signaling to sustain downstream Notch signals. Prior to their expression of T-bet, splenic cDC require cell-intrinsic Lymphotoxin beta receptor (LTbR) which is needed to reduce F-actin content and prevents the escape of cDC2 to the blood. We propose a novel mechanism whereby splenic cDC2-intrinsic LTbR signaling anchors cDC2 within the spleen so that they may access macromolecules such as retinol to promote cDC2A development.
2025-11-20 | GSE302089 | GEO