Dietary folate depletion and repletion in A/J and C57BL/6J mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE9242 | GEO | 2008/08/27
SECONDARY ACCESSION(S): PRJNA105253
REPOSITORIES: GEO
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Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis
2008-08-27 | GSE9243 | GEO
Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis Six-week old female A/J and C57BL/6J mice were purchased from the Jackson Laboratory. All mice were raised on a control diet containing four ppm folic acid (Basal Diet 5755, TestDiet) for one week before the start of studies. Selected mice were then placed on folic acid deficient diet (58C3, TestDiet) containing 1% succinylsulfathiazole, a non-absorbable antibiotic commonly used to suppress folate production by bacteria in the intestine. We had nine different treatment plans per strain with eight replicate mice per treatment. There were four folic acid depletion treatment in which mice were placed on folic acid deficient diet for 1, 2, 7, or 14 days. There were two folic acid repletion treatment in which mice were placed on folic acid deficient diet for 14 days followed by 1 day on control diet and another set of mice on 14 days of folic acid deficient diet followed by 7 days of control diet. There were three control time points in which mice were placed on the control diet for 0, 9, or 22 days. Eight biological replicate liver tissue from each treatment was pooled and total RNA from each pool and total RNA from Universal Mouse Reference RNA (Stratagene) were aminoallyl labeled with Cy3 and Cy5 in duplicate, with reversing of dyes.
2008-08-27 | E-GEOD-9242 | biostudies-arrayexpress
Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis Six-week old female C57BL/6J and B6.129P2-Apoetm1Unc/J (Piedrahita et al. 1992) mice were purchased from the Jackson Laboratory. All mice were raised on a control diet containing four ppm folic acid (Basal Diet 5755, TestDiet) for one week before the start of studies. Mice were then placed on folic acid deficient diet (58C3, TestDiet) containing 1% succinylsulfathiazole, a non-absorbable antibiotic commonly used to suppress folate production by bacteria in the intestine, for 14 days. A subset of these mice were placed back on control diet for 7 days after 14 day depletion. There were three groups of mice that underwent folic acid depletion and repletion. ApoE knockout mice on C57BL/6J background, C57BL/6J mice supplemented with 25mM choline and 50mM saccharine in drinking water, and C57BL/6J mice supplemented with 50mM saccharine. Saccharine was used to reduce the bitter taste of choline in the drinking water. We also had C57BL/6J mice on the control diet for 14 days and 21 days. These mice served as controls for treated mice from each time point during hybridization. The folate level in the control diet for this study was significantly lower than the previous study (GSE9242) due to greater loss of folic acid by irradiation of the diet. There were eight replicate mice per treatment group per folic acid perturbation protocol. An equal amount (by weight) of liver tissue from eight replicate mice was separated into two pools of four replicate tissues each. Pooled RNA from treated mice and pooled RNA from control mice for each time point were aminoallyl labeled with Cy3 and Cy5 in duplicate with reversing of dyes.
2008-08-27 | E-GEOD-9243 | biostudies-arrayexpress
Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism. 5 groups of NTD mutants were studied. From each mutant group Heterozygous (test) and wild-type (control) female pups were used for this study at 6-8 weeks of age. 4 biological replicates were used for each of the test and control groups of each mutant. All mice used for the experiments were fasted 4-5 hours before dissection. A total of 36 samples were analyzed.
2013-09-30 | E-GEOD-51285 | biostudies-arrayexpress
Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism.
2013-09-30 | GSE51285 | GEO
Project description:Background & Aims: Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied and the mechanisms by which this vitamin exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers. Methods: Hypergastrinemic mice (INS-GAS) infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer, with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation-sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements and immunohistochemistry (IHC) with anti-5-methylcytosine. We also profiled gene expression in the same tissues. Results: We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and IHC for lymphocyte markers. Conclusions: We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to reverse global loss of methylation and suppress inflammation. Study the difference in gene expression between transgenic hypergastrinemic (INS-GAS) mice fed a folate-supplemented diet and a diet with normal folate content. Because folate had a substantial protective effect, we matched the animals not only by folate status but also by dysplasia score (DYS). The degree of dysplasia was scored on a 1-4 scale. True replicates are not included. The first five samples are from folate supplemented animals, and the latter five are from controls on regular chow.
2011-07-20 | E-GEOD-30830 | biostudies-arrayexpress
Project description:Folate is crucial for diverse biological processes including neurogenesis. While folate supplementation during pregnancy is standard for preventing neural tube defects (NTDs), concerns are growing over the potential risks of excessive maternal intake. In this study, we employed spatial transcriptomics and single-nucleus multi-omics techniques to investigate the impact of increased maternal folate intake on offspring brain development. Elevated folate intake broadly affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions. Furthermore, specific gene expression alterations related to learning and memory processes emerged in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in dentate gyrus are particularly vulnerable to suboptimal maternal folate intake. Aberrant gene expression and chromatin accessibility changes were primarily centered on pathways governing ribosomal biogenesis, which is critical for synaptic formation. Altogether, our findings provide novel insights into how excessive maternal folate supplementation affects offspring brain development, notably by influencing gene expression and chromatin accessibility.
2024-07-10 | GSE269543 | GEO
Project description:Folate is crucial for diverse biological processes including neurogenesis. While folate supplementation during pregnancy is standard for preventing neural tube defects (NTDs), concerns are growing over the potential risks of excessive maternal intake. In this study, we employed spatial transcriptomics and single-nucleus multi-omics techniques to investigate the impact of increased maternal folate intake on offspring brain development. Elevated folate intake broadly affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions. Furthermore, specific gene expression alterations related to learning and memory processes emerged in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in dentate gyrus are particularly vulnerable to suboptimal maternal folate intake. Aberrant gene expression and chromatin accessibility changes were primarily centered on pathways governing ribosomal biogenesis, which is critical for synaptic formation. Altogether, our findings provide novel insights into how excessive maternal folate supplementation affects offspring brain development, notably by influencing gene expression and chromatin accessibility.
2024-07-10 | GSE269544 | GEO
Project description:The study evaluated effects of dietary cholesterol (1.5%) in Atlantic salmon fed a plant based diet for 77 days. Cholesterol supplementation did not affect growth or organ weights of Atlantic salmon, but promoted induction of cholesterol and plant sterol efflux in the intestine, whereas sterol uptake was suppressed. Microarray analyses in the liver indicated decreased cholesterol biosynthesis and enhanced conversion to bile acids. The marked effect of cholesterol on bile acid synthesis suggests that dietary cholesterol can be used to stimulate bile acid synthesis in fish. The study clearly demonstrated how Atlantic salmon adjusted metabolic functions in response to the dietary load of cholesterol, and has expanded our understanding of sterol metabolism and turnover that adds to the knowledge of these processes in fish. Atlantic salmon received feeds based on plant ingredients with (CH) and without (K) supplementation of cholesterol. Liver samples were collected after 77 days. Five individuals from each group were analyzed with microarrays, pooled liver sample of salmon fed with commerical fish meal based feed was used as a reference.
2013-10-31 | E-GEOD-51887 | biostudies-arrayexpress
Project description:We have previously shown that paramylon (PM) supplementation to a high fat diet reduces the postprandial glucose rise, serum total and LDL-cholesterol, and abdominal fat accumulation in mice; however, the mechanism has not been determined. We evaluated the potential mechanism in male C57BL/6J mice fed a high-fat diet supplemented with 5% PM powder, extracted from Eu-glena gracilis, for 12 weeks. Abdominal fat weight, and serum lipids were measured; ileal and hepatic mRNA expression were assessed using DNA microarray and real-time PCR. The poten-tial mechanism of PM on modulating lipid metabolism was explored by gene ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Dietary supplementation with PM resulted in decreased abdominal fat accumulation and serum LDL-cholesterol concentrations via suppression of the digestion and absorption pathway in the ileum and activation of the hepatic PPAR signaling pathway. Improvement in glucose tolerance may be the result of lipid metabolism modification because the glucose metabolism pathway was not detected by GO classification and KEGG pathway analysis. PM intake also directly enhanced immunoglobulin production.
2021-08-04 | GSE181289 | GEO