Effects of Chronic Hypervitaminosis a on Global Plasma Metabolome Changes and Liver Gene Expression (OR05-06-19)

Abstract Objectives Concerns about inadvertent chronic excessive vitamin A (VA) intakes due to overly frequent supplementation, fortification and voluntarily fortified products have been raised. Although chronic excessive VA intake can create liver abnormalities, clinically detectable signs of VA toxicity are rare, indicating the need for early biomarkers of tissue damage induced by excessive VA intake. Methods To identify early markers of VA toxicity, we induced chronic hypervitaminosis A in pigs (64 pigs, 8 per group) dosed with an oral supplement of retinyl propionate (0 up to 10,000 µg/KgBW) for 17 weeks. To assess the regulatory role of vitamin A in liver metabolism, a microarray analysis was performed to identify genetic regulation in liver tissue. Gene expression data were confirmed using qRT-PCR, and differentially expressed transcripts and pathways were identified using Genespring and Ingenuity Pathway Analysis (IPA). Additionally, two untargeted UPLC-MS assays (HILIC and C18 reversed phase) were applied to analyse plasma metabolites followed by univariate and multivariate analysis. Results Metabolomics analysis indicated that between 228 to 949 plasma metabolites were statistically significant between VA treated and control animals. The majority of metabolic changes observed in plasma were lipids, with ceramides, glycerophospholipids, lysoglycerophospholipids, sterol lipids and triacylglycerides enriched in both low and high VA dosed animals. Gene expression analysis confirmed significant changes in lipid metabolism, with pathways in metabolism of terpenoids and membrane lipids significantly increased by 2.4 fold. Conclusions The combined analysis of gene expression with untargeted metabolomics data confirm that changes in liver function and lipid metabolism offers an opportunity to develop a biomarker panel to diagnose pre-symptomatic hypervitaminosis A in humans. Funding Sources Supported by the Bill and Melinda Gates foundation.

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The Effect of Chronic High Dose Vitamin a Supplementation on Lipid Metabolism in Adipose Tissue (P02-013-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz029.p02-013-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Kieran Finney ◽

Anthony Oxley ◽

Catherine Winder ◽

Andrew Southam ◽

Andris Jankevics ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Vitamin A ◽

Mitochondrial Dysfunction ◽

High Dose ◽

Serum Samples ◽

Hypervitaminosis A ◽

The Impact ◽

High Dose Vitamin

Abstract Objectives The objective of this study was to assess the impact of high-dose vitamin A (VA) on lipid metabolism. Previously, VA has been shown to enhance fat mobilisation, leading to a reduction in body fat. We hypothesise that hypervitaminosis A will increase expression of genes associated with lipid catabolism. Methods To induce chronic hypervitaminosis A, two groups of pigs (n = 8) were fed a commercial diet. The treatment group was additionally dosed, daily, with an oral supplement of retinyl propionate of 10,000 µg/KgBW for 17 weeks. To assess the impact of VA on lipid metabolism, a microarray analysis was performed to identify gene expression in adipose tissue. Differentially expressed transcripts and pathways were identified using Genespring and mapped to human orthologues for Ingenuity Pathway Analysis (IPA); gene fold changes were confirmed using qRT-PCR. Additionally, an untargeted UPLC-MS lipidomic analysis was carried out in serum samples to identify changes in lipd classes and their metabolites. Results In dosed animals, significant increases in plasma retinol (0.66 μmol/L) and liver retinyl ester concentrations (11.98 μmol/g both P < 0.001), as well as an increase in serum NEFA of 92.84 μmol/L (P = 0.001) were observed. Gene expression fold changes in subcutaneous adipose tissue were related to mitochondrial dysfunction and lipid metabolism, including increased expression of MT-CYTB (↑4.78x, P < 0.05) and ATP5A1 (↑3.13x, P < 0.05). Metabolomics confirmed changes in lipids and their metabolites relevant to adipose tissue in blood (P = 0.05), namely a decrease in triacylglyceride concentration and increases in acyl carnitine and cardiolipin concentrations. Conclusions An integrated pathway is suggested to explain the role of vitamin A in leading to increased lipolysis, β-oxidation and oxidative phosphorylation, but when in excess, markers of mitochondrial dysfunction were observed. Funding Sources Funded by the Bill and Melinda Gates foundation.

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Increased Risk of High Body Fat and Altered Lipid Metabolism Associated to Suboptimal Consumption of Vitamin A Is Modulated by Genetic Variants rs5888 (SCARB1), rs1800629 (UCP1) and rs659366 (UCP2)

Nutrients ◽

10.3390/nu12092588 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2588

Author(s):

Sebastià Galmés ◽

Andreu Palou ◽

Francisca Serra

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Vitamin A ◽

Body Fat ◽

Genetic Variants ◽

Mononuclear Cells ◽

Metabolic Response ◽

Ex Vivo ◽

P Value ◽

Increased Risk

Obesity is characterized by an excessive body fat percentage (BF%). Animal and cell studies have shown benefits of vitamin A (VA) on BF% and lipid metabolism, but it is still controversial in humans. Furthermore, although some genetic variants may explain heterogeneity in VA plasma levels, their role in VA metabolic response is still scarcely characterized. This study was designed as a combination of an observational study involving 158 male subjects followed by a study with a well-balanced genotype–phenotype protocol, including in the design an ex vivo intervention study performed on isolated peripheral blood mononuclear cells (PBMCs) of the 41 former males. This is a strategy to accurately identify the delivery of Precision Nutrition recommendations to targeted subjects. The study assesses the influence of rs5888 (SCARB1), rs659366 (UCP2), and rs1800629 (UCP1) variants on higher BF% associated with suboptimal VA consumption and underlines the cellular mechanisms involved by analyzing basal and retinoic acid (RA) response on PBMC gene expression. Data show that male carriers with the major allele combinations and following suboptimal-VA diet show higher BF% (adjusted ANOVA test p-value = 0.006). Genotype–BF% interaction is observed on oxidative/inflammatory gene expression and also influences lipid related gene expression in response to RA. Data indicate that under suboptimal consumption of VA, carriers of VA responsive variants and with high-BF% show a gene expression profile consistent with an impaired basal metabolic state. The results show the relevance of consuming VA within the required amounts, its impact on metabolism and energy balance, and consequently, on men’s adiposity with a clear influence of genetic variants SCARB1, UCP2 and UCP1.

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Effect of nutritional vitamin A deficiency on lipid metabolism in the rat heart: Its relation to PPAR gene expression

Nutrition ◽

10.1016/j.nut.2009.01.008 ◽

2009 ◽

Vol 25 (7-8) ◽

pp. 828-838 ◽

Cited By ~ 17

Author(s):

Verónica Analía Vega ◽

Ana Cecilia Anzulovich ◽

Silvia Mabel Varas ◽

Mirtha Ruth Bonomi ◽

María Sofía Giménez ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Vitamin A ◽

Rat Heart ◽

Vitamin A Deficiency ◽

Nutritional Vitamin

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The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives

Current Drug Targets ◽

10.2174/1389450120666181217095323 ◽

2019 ◽

Vol 20 (8) ◽

pp. 871-878 ◽

Cited By ~ 1

Author(s):

Pedro Xavier-Elsas ◽

Bruno M. Vieira ◽

Daniela Masid-de-Brito ◽

Monica G. Barradas ◽

Maria I.C. Gaspar-Elsas

Keyword(s):

Vitamin A ◽

Clinical Presentation ◽

Infectious Agents ◽

Hypervitaminosis A ◽

General Role ◽

Significant Toxicity ◽

Vast Literature ◽

Gut Mucosa ◽

Anti Inflammatory ◽

Pathogen Exposure

Vitamin A and its derivatives (retinoids) act as potent regulators in many aspects of mammalian reproduction, development, repair, and maintenance of differentiated tissue functioning. Unlike other vitamins, Vitamin A and retinoids, which have hormonal actions, present significant toxicity, which plays roles in clinically relevant situations, such as hypervitaminosis A and retinoic acid ("differentiation") syndrome. Although clinical presentation is conspicuous in states of insufficient or excessive Vitamin A and retinoid concentration, equally relevant effects on host resistance to specific infectious agents, and in the general maintenance of immune homeostasis, may go unnoticed, because their expression requires either pathogen exposure or the presence of inflammatory co-morbidities. There is a vast literature on the roles played by retinoids in the maintenance of a tolerogenic, noninflammatory environment in the gut mucosa, which is considered by many investigators representative of a general role played by retinoids as anti-inflammatory hormones elsewhere. However, in the gut mucosa itself, as well as in the bone marrow and inflammatory sites, context determines whether one observes an anti-inflammatory or proinflammatory action of retinoids. Both interactions between specialized cell populations, and interactions between retinoids and other classes of mediators/regulators, such as cytokines and glucocorticoid hormones, must be considered as important factors contributing to this overall context. We review evidence from recent studies on mucosal immunity, granulocyte biology and respiratory allergy models, highlighting the relevance of these variables as well as their possible contributions to the observed outcomes.

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Dietary n‐3 long chain polyunsaturated fatty acids affect the serum biochemical parameters, lipid‐metabolism‐related of gene expression and intestinal health of juvenile hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatu )

Aquaculture Nutrition ◽

10.1111/anu.13276 ◽

2021 ◽

Author(s):

Wenqiang An ◽

Xiaohui Dong ◽

Beiping Tan ◽

Qihui Yang ◽

Shuyan Chi ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acids ◽

Lipid Metabolism ◽

Polyunsaturated Fatty Acids ◽

Biochemical Parameters ◽

Serum Biochemical Parameters ◽

Hybrid Grouper ◽

Epinephelus Fuscoguttatus ◽

Serum Biochemical ◽

Long Chain

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Lipid Remodeling Confers Osmotic Stress Tolerance to Embryogenic Cells during Cryopreservation

International Journal of Molecular Sciences ◽

10.3390/ijms22042174 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2174

Author(s):

Liang Lin ◽

Junchao Ma ◽

Qin Ai ◽

Hugh W. Pritchard ◽

Weiqi Li ◽

...

Keyword(s):

Lipid Metabolism ◽

Technology Development ◽

Membrane Lipids ◽

Species Conservation ◽

Membrane Lipid ◽

Cell Integrity ◽

Embryogenic Cells ◽

Osmotic Stress Tolerance ◽

Lipid Species ◽

Magnolia Officinalis

Plant species conservation through cryopreservation using plant vitrification solutions (PVS) is based in empiricism and the mechanisms that confer cell integrity are not well understood. Using ESI-MS/MS analysis and quantification, we generated 12 comparative lipidomics datasets for membranes of embryogenic cells (ECs) of Magnolia officinalis during cryogenic treatments. Each step of the complex PVS-based cryoprotocol had a profoundly different impact on membrane lipid composition. Loading treatment (osmoprotection) remodeled the cell membrane by lipid turnover, between increased phosphatidic acid (PA) and phosphatidylglycerol (PG) and decreased phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The PA increase likely serves as an intermediate for adjustments in lipid metabolism to desiccation stress. Following PVS treatment, lipid levels increased, including PC and PE, and this effectively counteracted the potential for massive loss of lipid species when cryopreservation was implemented in the absence of cryoprotection. The present detailed cryobiotechnology findings suggest that the remodeling of membrane lipids and attenuation of lipid degradation are critical for the successful use of PVS. As lipid metabolism and composition varies with species, these new insights provide a framework for technology development for the preservation of other species at increasing risk of extinction.

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CFTR Modulator Therapy with Lumacaftor/Ivacaftor Alters Plasma Concentrations of Lipid-Soluble Vitamins A and E in Patients with Cystic Fibrosis

Antioxidants ◽

10.3390/antiox10030483 ◽

2021 ◽

Vol 10 (3) ◽

pp. 483

Author(s):

Olaf Sommerburg ◽

Susanne Hämmerling ◽

S. Philipp Schneider ◽

Jürgen Okun ◽

Claus-Dieter Langhans ◽

...

Keyword(s):

Cystic Fibrosis ◽

Vitamin E ◽

Vitamin A ◽

Clinical Chemistry ◽

Pancreatic Insufficiency ◽

Plasma Concentrations ◽

Plasma Vitamin ◽

Hypervitaminosis A ◽

Cholesterol Ratio ◽

Fat Soluble Vitamins

Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

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The Feasibility of Studying Metabolites in PICU Multi-Organ Dysfunction Syndrome Patients over an 8-Day Course Using an Untargeted Approach

Children ◽

10.3390/children8020151 ◽

2021 ◽

Vol 8 (2) ◽

pp. 151

Author(s):

Mara Leimanis-Laurens ◽

Danny Gil ◽

Andrew Kampfschulte ◽

Claire Krohn ◽

Elizabeth Prentice ◽

...

Keyword(s):

Organ Dysfunction ◽

Repeated Measures ◽

Pediatric Intensive Care ◽

Reversed Phase ◽

Outpatient Setting ◽

Plasma Metabolites ◽

Internal Validation ◽

Bonferroni Adjustment ◽

Pediatric Study ◽

Multi Organ Dysfunction Syndrome

Metabolites are generated from critical biological functions and metabolism. This pediatric study reviewed plasma metabolites in patients suffering from multi-organ dysfunction syndrome (MODS) in the pediatric intensive care unit (PICU) using an untargeted metabolomics approach. Patients meeting the criteria for MODS were screened for eligibility and consented (n = 24), and blood samples were collected at baseline, 72 h, and 8 days; control patients (n = 4) presented for routine sedation in an outpatient setting. A subset of MODS patients (n = 8) required additional support with veno-atrial extracorporeal membrane oxygenation (VA-ECMO) therapy. Metabolites from thawed blood plasma were determined from ion pairing reversed-phase liquid chromatography–mass spectrometry (LC-MS) analysis. Chromatographic peak alignment, identification, relative quantitation, and statistical and bioinformatics evaluation were performed using MAVEN and MetaboAnalyst 4.0. Metabolite analysis revealed 115 peaks per sample. From the partial least squares-discriminant analysis (PLS-DA) with variance of importance (VIP) scores above ≥2.0, 7 dynamic metabolites emerged over the three time points: tauro-chenodeoxycholic acid (TCDCA), hexose, p-hydroxybenzoate, hydroxyphenylacetic acid (HPLA), 2_3-dihydroxybenzoic acid, 2-keto-isovalerate, and deoxyribose phosphate. After Bonferroni adjustment for repeated measures, hexose and p-hydroxybenzoate were significant at one time point or more. Kendall’s tau-b test was used for internal validation of creatinine. Metabolites may be benign or significant in describing a patient’s pathophysiology and require operator interpretation.

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South African preschool children habitually consuming sheep liver and exposed to vitamin A supplementation and fortification have hypervitaminotic A liver stores: a cohort study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy382 ◽

2019 ◽

Vol 110 (1) ◽

pp. 91-101 ◽

Cited By ~ 10

Author(s):

Martha E van Stuijvenberg ◽

Muhammad A Dhansay ◽

Jana Nel ◽

Devika Suri ◽

Michael Grahn ◽

...

Keyword(s):

South Africa ◽

Preschool Children ◽

Vitamin A ◽

Total Serum ◽

High Dose ◽

Serum Retinol ◽

Hypervitaminosis A ◽

Total Liver ◽

Before And After ◽

Retinyl Esters

ABSTRACT Background In some regions, multiple vitamin A (VA) interventions occur in the same target groups, which may lead to excessive stores. Retinol isotope dilution (RID) is a more sensitive technique than serum retinol to measure VA status. Objective We evaluated VA status before and after a high-dose supplement in preschool children living in a region in South Africa with habitual liver consumption and exposed to VA supplementation and fortification. Methods After baseline blood samples, subjects (46.7 ± 8.4 mo; n = 94) were administered 1.0 μmol [14,15]-13C2-retinyl acetate to estimate total liver retinol reserves by RID with a follow-up 14-d blood sample. Liver intake was assessed with a frequency questionnaire. In line with current practice, a routine 200,000 IU VA capsule was administered after the RID test. RID was repeated 1 mo later. Serum retinyl esters were evaluated using ultra-performance liquid chromatography. Results At baseline, 63.6% of these children had hypervitaminosis A defined as total liver retinol reserves ≥1.0 μmol/g liver, which increased to 71.6% after supplementation (1.13 ± 0.43 to 1.29 ± 0.46 μmol/g; P < 0.001). Total serum VA as retinyl esters was elevated in 4.8% and 6.1% of children before and after supplementation. The odds of having hypervitaminosis A at baseline were higher in children consuming liver ≥1/mo (ratio 3.70 [95% CI: 1.08, 12.6]) and in children receiving 2 (4.28 [1.03, 17.9]) or 3 (6.45 [0.64, 65.41]) supplements in the past 12 mo. Total body stores decreased after the supplement in children in the highest quartile at baseline compared with children with lower stores, who showed an increase (P = 0.007). Conclusions In children, such as this cohort in South Africa, with adequate VA intake through diet, and overlapping VA fortification and supplementation, preschool VA capsule distribution should be re-evaluated. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT02915731 as NCT02915731.

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