Supplementary Table 2. Excluded studies and reasons for exclusion Author(s) and YearReason for exclusion Damms-Machado et al. (2012) Overlaps with other studies Török et al. (2003) Unable to retrieve paper Couillard et al. (2016) Unable to retrieve paper Morinobu et al. (2002) Unable to retrieve paper Gu et al. (1999) Unable to retrieve paper Hooper et al. (1983) Unable to retrieve paper Lowenstein (1981) Unable to retrieve paper Luna et al. (2012) Unable to retrieve paper Mehta and Shringarpure (2000) Unable to retrieve paper Mannisto et al. (1997) Unable to retrieve paper Kimmons et al. (2006) Only reported odd ratios Park et al. (2008) Reported data based on liver fat and not whole body adiposity. Higuchi et al. (2015) Only reported odd ratios. Xiao et al. (2018) Study did not include a control group. Suriyaprom et al. (2014) Unable to retrieve despite all efforts Lefebvre et al. (2014) Unable to retrieve despite all efforts Yeum et al. (1998) Reported data based on breast cancer and not whole body adiposity. Danquah et al. (2015) Control and intervention group had almost identical body weights Abahusain et al. (1999) Control and intervention group had almost identical body weights Fernández-Bañares et al. (1994) Unable to retrieve Shehata et al. (2016) Unable to retrieve Wolf et al. (2015) Study did not include a control group Ford et al. (1999) Overlaps with other studies Han et al. (2016) Overlaps with other studies Wang et al. (2006) Overlaps with other studies Aeberli et al. (2006) Overlaps with other studies Järvinen et al. (1994) Unsuitable/unidentifiable weight definition for control and comparator group. Basualdo et al. (1997) Control group BMI was within the overweight range. Reunanen et al. (1998) Control group BMI was within the overweight range.
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.
The proposed protocol is for a systematic review and meta-analysis on the relationship between vitamin A and body mass. The primary objective is to explore the mechanisms between vitamin A and adiposity such as inflammation, dietary intake and body fat. The secondary objective is to look at the extent to which vitamin A is stored in different adipose tissue depots. The protocol outlines the motive and scope for the review, and methodology including the risk of bias, statistical analysis, screening and study criteria. Background 1 The problem, condition or issueGlobally, an estimated 1.9 billion people are either overweight or obese (WHO et al, 2017). It is well known that obesity is a leading cause for many non-communicable chronic diseases (NCDs) including cardiovascular disease, hypertension, type 2 diabetes (T2D) and cancer. More recently, micronutrient deficiency has been found in obese individuals in Vietnam and Latin American countries such as Mexico and Brazil (Laillou et al, 2014;Garcia et al, 2013;de Souza et al, 2007).Together, these two burdens constitute the double burden of malnutrition. There is increasing evidence indicating an inverse association between micronutrients and individuals with a higher body mass index (BMI), in particular fat soluble vitamins such as vitamin A (Andersen et al, 2006; Suzuki et al, 2006). These studies have also shown that dietary intakes of normal weight, overweight and obese individuals are not drastically different. Moreover, animal studies confirmed that obesity causes vitamin A deficiency, as vitamin A levels and transcriptional signalling is reduced in multiple organs, when serum vitamin A concentrations are in the normal range (Trasino et al, 2015).In humans, low serum vitamin A concentrations have been observed in obese individuals, most likely due to increased uptake into the adipose tissue depot, which is acting as a major body pool for vitamin A (Osth et al, 2014;Bonet et al, 2012;Bonet et al, 2003). Although, there is considerable evidence showing similar observations for other vitamins such as vitamin D, vitamin A plays a key role in the regulation of genes involved in fatty acid oxidation and lipid metabolism (Saneei et al, 2013). Vitamin A has been shown to be associated with a reduced odds of metabolic syndrome (MS), non alcoholic fatty acid liver disease (NAFLD) and dyslipidemia (Beydoun et al, 2012;Botella-Carretero et al, 2010;Albuquerque et al, 2016). Therefore, adequate vitamin A status in key metabolic tissues may lead to favourable reductions in body fat and subsequently reductions in obesity.However, it is not clear if an increase in adiposity is a causal effect of low serum vitamin A concentrations or the result of other physiological and environmental factors (Garcia et al, 2009). For instance, inflammation and dietary intake have been implicated as reasons for reduced serum vitamin A concentrations (Hosseini et al, 2017). Therefore, the proposed review hopes to show the degree at which inflammation and dietary intake each effect seru...
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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