scholarly journals The Effect of Chronic High Dose Vitamin a Supplementation on Lipid Metabolism in Adipose Tissue (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.

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

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Georg Lietz ◽  
Anthony Oxley ◽  
Kieran Finney ◽  
Adam Clark ◽  
Tim Giles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Vitamin A ◽  
Membrane Lipids ◽  
Genetic Regulation ◽  
Reversed Phase ◽  
Plasma Metabolites ◽  
Hypervitaminosis A ◽  
Metabolomics Data ◽  
Gates Foundation

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.

scholarly journals High dose vitamin A capsules – Rusty bullets?

2017 ◽  
Vol 8 (1) ◽  
pp. 52
Author(s):  
Ane B Fisker ◽  
Ted Greiner
Keyword(s):  
Vitamin A ◽  
Low Income ◽  
Vitamin A Deficiency ◽  
Scale Up ◽  
Low Income Countries ◽  
High Dose ◽  
Magic Bullet ◽  
Vitamin A Status ◽  
The Impact ◽  
High Dose Vitamin

High-dose vitamin A capsules (HDVAC) are distributed to preschool children in low-income countries on the assumption that they reduce mortality and treat vitamin A deficiency. As for other so-called magic bullet approaches, donors and policy makers consider their large-scale distribution highly cost-effective. Consequently, other ways to improve vitamin A status have received less attention; both donors and governments assume HDVAC are doing most of what needs to be done. Yet, the only evidence for an effect on mortality comes from 25-year-old studies and this effect no longer appears to be substantial. Surprisingly, impact evaluations have been absent. The only study that might be considered an effectiveness or impact evaluation found HDVAC had no effect in northern India. It is not widely appreciated that the impact of HDVAC on vitamin A status is limited, temporary and not cumulative over time. Nor can it be given to women except immediately after giving birth, and thus it is an inappropriate intervention for tackling vitamin A deficiency. To ensure that we use limited resources wisely, we need to identity and scale up strategies which combat vitamin A deficiency and reduce mortality.

scholarly journals Tartary Buckwheat Extract Attenuated the Obesity-Induced Inflammation and Increased Muscle PGC-1a/SIRT1 Expression in High Fat Diet-Induced Obese Rats

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 654 ◽  
Author(s):  
Seog-Young Kim ◽  
Mak-Soon Lee ◽  
Eugene Chang ◽  
Sunyoon Jung ◽  
Hyunmi Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Tartary Buckwheat ◽  
High Dose ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Gene Markers ◽  
Tissue Inflammation

Obesity is intimately related to a chronic inflammatory state, with augmentation of macrophage infiltration and pro-inflammatory cytokine secretion in white adipose tissue (WAT) and mitochondrial dysfunction in skeletal muscle. The specific aim of this study is to evaluate effects of tartary buckwheat extract (TB) on obesity-induced adipose tissue inflammation and muscle peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α/sirtulin 1 (SIRT1) pathway in rats fed a high-fat diet. Sprague-Dawley rats were divided into four groups and fed either a normal diet (NOR), 45% high-fat diet (HF), HF + low dose of TB (TB-L; 5 g/kg diet), or HF + high dose of TB (TB-H; 10 g/kg diet) for 13 weeks. TB significantly reduced adipose tissue mass with decreased adipogenic gene expression of PPAR-γ and aP2. Serum nitric oxide levels and adipose tissue macrophage M1 polarization gene markers, such as iNOS, CD11c, and Arg1, and pro-inflammatory gene expression, including TNF-α, IL-6, and MCP-1, were remarkably downregulated in the TB-L and TB-H groups. Moreover, TB supplementation increased gene expression of PGC-1α and SIRT1, involved in muscle biogenesis and function. These results suggested that TB might attenuate obesity-induced inflammation and mitochondrial dysfunction by modulating adipose tissue inflammation and the muscle PGC-1α/SIRT1 pathway.

scholarly journals Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David Machover ◽  
Wathek Almohamad ◽  
Vincent Castagné ◽  
Christophe Desterke ◽  
Léa Gomez ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Digestive Tract ◽  
Vitamin B6 ◽  
Colorectal Adenocarcinoma ◽  
High Dose ◽  
High Concentration ◽  
Carcinoma Of The Esophagus ◽  
Pancreas Adenocarcinoma ◽  
The Impact ◽  
High Dose Vitamin

AbstractSupplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. We report a pilot study in 13 patients with previously untreated advanced carcinoma of the digestive tract to assess the impact of high-dose pyridoxine (PN) on the antitumor activity of regimens comprising FUra and FA. Five patients had colorectal adenocarcinoma (CRC); 5 had pancreas adenocarcinoma (PC); and 3 had squamous cell carcinoma of the esophagus (EC). Patients with CRC and with PC received oxaliplatin, irinotecan, FUra and FA, and patients with EC had paclitaxel, carboplatin, FUra and FA. PN iv from 1000 to 3000 mg/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates ≥ 78%. Two patients with PC attained CRs, and 2 had PRs with reduction rates ≥ 79%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3 months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.

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

2019 ◽  
Vol 110 (1) ◽  
pp. 91-101 ◽  
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.

scholarly journals Identification of Novel GH-Regulated Pathway of Lipid Metabolism in Adipose Tissue: A Gene Expression Study in Hypopituitary Men

2011 ◽  
Vol 96 (7) ◽  
pp. E1188-E1196 ◽  
Author(s):  
Jing Ting Zhao ◽  
Mark J. Cowley ◽  
Paul Lee ◽  
Vita Birzniece ◽  
Warren Kaplan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Gene Expression Study ◽  
Expression Study

Abstract 74: The Nox4 Inhibitor GKT137831, Prevents Aldosterone Production by Adipocytes and Protects Against Adipose Tissue Inflammation and Fibrosis in Obese Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sarah Even ◽  
Aurelie Nguyen Dinh Cat ◽  
Francisco J Rios ◽  
Antunes T Tayze ◽  
Ying He ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Culture Media ◽  
Inflammatory Marker ◽  
High Dose ◽  
Obese Mice ◽  
Cardiovascular Damage ◽  
Aldosterone Production ◽  
Inflammatory Phenotype ◽  
Sirius Red

Aldosterone (aldo) plays an important role in obesity-associated cardiovascular risk. We demonstrated that aldo is produced by adipocytes, an effect associated with increased generation of reactive oxygen species (ROS). These processes are exaggerated in obesity. The relationship between adipocyte aldosterone and ROS is unclear. We postulated that Nox4-derived ROS is important for aldo production in adipocytes and leads to a pro-inflammatory phenotype in obesity. Studies were performed in db/m (lean) and db/db (obese) mice, treated with low (20mg/kg/day) or high dose (60mg/kg/day) GKT137831 (GKT, Nox4 inhibitor, 16 weeks). Epididymal (EVAT) and perivascular (PVAT) fat were collected. Plasma and adipocyte aldo were measured by ELISA. Adipose tissue fibrosis was evaluated by picro Sirius red staining and inflammatory mediators by immunostudies. Body weight was increased in db/db mice (61.8g vs control 33.5g), with no effect of GKT. Epididymal adiposity was increased in db/db mice (0.098g vs. 0.067g, p<0.05). Plasma aldo levels in db/db (pg/mL: 518 vs. 272g) and aldo levels in culture media from db/db adipocytes were increased (pg/mL/μg RNA: 1964 vs. 388), p<0.05. All effects decreased by high dose GKT. In PVAT, CYP11B2 gene expression was increased in db/db (2.6±0.8 vs control 1.1±0.1, p<0.05), an effect blocked by Nox4 inhibition. Gene expression of adipocyte differentiation marker, AP2, was increased (3.5±1.1 vs control 1.4±0.4) while anti-inflammatory marker adiponectin was decreased (0.7±0.1 vs control 1.3±0.2, p<0.05)) in obese mice. GKT decreased AP2 levels. Adipocyte-derived TNFα was increased in db/db (4.9±1.8 vs control 1.6±0.6, p<0.05), an effect blocked by GKT. Pro-collagen I, marker of fibrosis, was increased in db/db mice (132±11 vs control 87±4, p<0.05). Sirius red staining was exaggerated in EVAT from db/db mice, and decreased by Nox4 inhibition. In conclusion, Nox4 plays a role in regulating adipocyte-derived aldosterone and promotes a pro-inflammatory and profibrotic adipose phenotype in obese db/db mice. These findings suggest that adipocyte Nox4 links hyperaldosteronism and inflammation/fibrosis in adiposity and as such may be a putative therapeutic target for obesity-associated cardiovascular damage.

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