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Osmotic regulation of hepatic choline metabolism

ABSTRACT: Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. This study investigates to what extent hepatocellular hydration changes affect the expression levels of enzymes involved in the metabolism of betaine and related organic osmolytes by using qRT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in 5,10 - methylene tetrahydrofolate reductase (MTHFR) deficient primary hepatocytes. The results demonstrate a coordinated regulation of betaine degradation and synthesis under anisoosmotic conditions. Expression of betaine degrading enzymes is downregulated by hyperosmolarity and strongly induced by hypoosmolarity. In contrast, synthesis of glycerophosphocholine from phosphoethanolamine and conversion of choline to betaine are both induced by hyperosmolarity but decreased under hypoosmotic conditions. In addition we evaluated the flux of choline and its derivates in liver and plasma of methylene tetrahydrofolate reductase knockout (Mthfr-/-) mice by tandem mass spectrometry. Analyses of system-wide alterations of osmolyte metabolism with microarray studies revealed expression changes similar to those after hypoosmotic exposure in this betaine depletion model. In conclusion, regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations contribute to long-term adaptation to anisoosmotic exposure of the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE42275 | GEO | 2013/04/01

SECONDARY ACCESSION(S): PRJNA179514

REPOSITORIES: GEO

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Osmotic regulation of hepatic choline metabolism

Project description:Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. This study investigates to what extent hepatocellular hydration changes affect the expression levels of enzymes involved in the metabolism of betaine and related organic osmolytes by using qRT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in 5,10 - methylene tetrahydrofolate reductase (MTHFR) deficient primary hepatocytes. The results demonstrate a coordinated regulation of betaine degradation and synthesis under anisoosmotic conditions. Expression of betaine degrading enzymes is downregulated by hyperosmolarity and strongly induced by hypoosmolarity. In contrast, synthesis of glycerophosphocholine from phosphoethanolamine and conversion of choline to betaine are both induced by hyperosmolarity but decreased under hypoosmotic conditions. In addition we evaluated the flux of choline and its derivates in liver and plasma of methylene tetrahydrofolate reductase knockout (Mthfr-/-) mice by tandem mass spectrometry. Analyses of system-wide alterations of osmolyte metabolism with microarray studies revealed expression changes similar to those after hypoosmotic exposure in this betaine depletion model. In conclusion, regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations contribute to long-term adaptation to anisoosmotic exposure of the liver. Expression of 280 genes were analyzed in wild type and mthr-/- mice (n=7) with spotted oligonucleotides.

2013-04-01 | E-GEOD-42275 | biostudies-arrayexpress

Allergic Airway Disease is Dependent on Methylene-Tetrahydrofolate Reductase (expression)

Project description:RATIONALE: The development and progression of asthma are strongly influenced by environmental exposures. We have demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. OBJECTIVES: Since there is conflicting evidence on the role of folate in modifying allergic airway disease risk, we hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (MTHFR) activity would reduce the allergic airway disease phenotype. METHODS: Using a house dust mite (HDM) induced model of allergic airway disease, we tested the effect of MTHFR on disease severity. MEASUREMENTS AND MAIN RESULTS: Loss of MTHFR alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6MTHFR-/- mice demonstrate significantly less airway hyerreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6MTHFR-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and IL-4/IL-5 cytokine concentrations. The effect of MTHFR loss on HDM-induced allergic airway disease was reversed by betaine supplementation. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6MTHFR-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations. CONCLUSION: Collectively, these findings indicate that single carbon metabolism warrants further investigation as a disease modifier in allergic airway disease.

2018-01-31 | GSE71822 | GEO

Allergic Airway Disease is Dependent on Methylene-Tetrahydrofolate Reductase (Bisulfite-Seq)

2018-01-31 | GSE71821 | GEO

Maternal folic acid mild over consumption in mice leads to sex-specific transcriptional alterations in embryonic placenta

Project description:Food fortification and increased use of multivitamins have led to concerns over high folate intake periconceptionally. We reported that diets containing 5-fold higher FA than recommended for mice (5xFASD) during pregnancy, resulted in deficiency of methylenetetrahydrofolate reductase (MTHFR) and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. Our goal was to determine whether these changes had their origins in the placenta during embryonic development. We used microarrays to compare the placental gene expression changes by 5xFASD and indentified different gene expression profiles due to diet or sex.

2021-06-11 | GSE164408 | GEO

Systems-level Responses to Salinity and Temperature Variations in the Marine Bacterium Vibrio natriegens

Project description:Vibrio natriegens strain ATCC 14048 is a salt marsh isolate with a notably rapid growth rate that has garnered considerable interest for biotechnological applications. We used systems-level tools (i.e. metabolomics, transcriptomics, proteomics) to characterize its physiological response to different salinities and temperatures that are relevant not only to its natural environment but also to planned scalable culturing processes. We found organic osmolyte synthesis and membrane transporters were most responsive to changes in salinity. The osmolytes glutamate, glutamine and ectoine responded to salinity across temperature treatments. However, when media was supplemented with choline, glycine betaine appeared to replace ectoine. These results provide a baseline data set for metabolic activity under a variety of conditions that will influence future basic and applied V. natriegens research.

2021-09-18 | GSE184146 | GEO

Vibrio natriegens Systems & Synthetic Biology: Proteome Profile (Temperature & Salinity)

Project description:Vibrio natriegens is a rapidly growing salt marsh bacterium that is being developed as a synthetic biology chassis. We characterized its physiological response to different salinities and temperatures in order to optimize culturing conditions and understand its adaptations to a salt marsh environment. Using metabolomics, transcriptomics, and proteomics we determined what pathways respond to these environmental parameters. We found that organic osmolyte synthesis and membrane transporters were most responsive to changes in salinity. The primary osmolytes were glutamate, glutamine, and ectoine, responding to salinity across temperature treatments. However, when media was supplemented with choline, glycine betaine seemed to mostly replace ectoine. These results provide a baseline dataset of metabolic activity under a variety of conditions that will inform decisions made about culturing and genome engineering for future applications.

2021-09-15 | PXD027874 | Pride

Enuh2022-PHB and Osmoprotectant metabolism model of Chromohalobacter canadensis

Project description:This model is the first of Chromohalobacter canadensis. The pathways for PHB mtabolism, and osmoprotectants (ectoine, betaine, choline) were curated.

2022-09-27 | MODEL2204110001 | BioModels

The effects of UVB and the organic osmolyte betaine on rat epidermal keratinocytes in an organotypic culture system

Project description:Betaine (trimethylglycine) is a non-toxic, highly water-soluble organic osmolyte widely used in skin care due to its assumed moisturizing and protective properties, but only few studies have addressed its specific effects in skin. Here, the cellular and molecular targets of betaine were analyzed by genome-wide expression analysis in organotypic cultures of rat epidermal keratinocytes (REK). In this model, we also examined whether betaine modifies the impacts of acute UVB exposure. The expression of several genes relevant to epidermal biology, proliferation/differentiation or malignancy as well as solute transport were verified by independent methods (qRT-PCR, western blotting). The data concerning changes in calcium metabolism after UVB exposure has been published separately (Bart et al., Br. J. Dermatol. 171:376-387, 2014).

2015-10-26 | GSE63004 | GEO

Influence of glycine betaine on the transcriptional profile of the Bacillus subtilis SigB regulon

Project description:To investigate whether salt-stress dependent activation of SigB is mitigated when cells are pre-loaded with the compatible solute glycine betaine, we analyzed salt induction of the SigB regulon in the presence of the precursor choline at a genome-wide level. The median expression value of SigB-regulated genes was 1.7-fold higher in cells that received choline immediately before salt stress compared to cells where choline was added 60 minutes prior to the salt stress.

2020-03-01 | GSE141882 | GEO

Paternal MTHFR deficiency leads to reproductive decline across generations in association with hypomethylation of young retrotransposons

Project description:5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations. While MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late prenatal germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in prenatal germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR- deficient males, findings compatible with the intergenerational passage of epimutations.

2021-06-28 | GSE166586 | GEO

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