Alterations in One-Carbon Metabolism in Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy associated with alterations of metabolism. Metabolomics studies, although limited, showed changes in choline, choline-derived lipids, and methionine concentrations, which could be ascribed to alterations in one-carbon metabolism. To date, no targeted metabolomics analysis investigating differences in the plasma choline/methionine metabolome of CD subjects are reported. This work is a targeted metabolomic study that analyzes 37 metabolites of the one-carbon metabolism in 17 children with CD, treated with a gluten-free diet and 17 healthy control siblings, in order to establish the potential defects in this metabolic network. Our results demonstrate the persistence of defects in the transsulfuration pathway of CD subjects, despite dietary treatment, while choline metabolism, methionine cycle, and folate cycle seem to be reversed and preserved to healthy levels. These findings describe for the first time, a metabolic defect in one-carbon metabolism which could have profound implications in the physiopathology and treatment of CD.

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One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

Cells ◽

10.3390/cells11020214 ◽

2022 ◽

Vol 11 (2) ◽

pp. 214

Author(s):

Eirini Lionaki ◽

Christina Ploumi ◽

Nektarios Tavernarakis

Keyword(s):

Carbon Metabolism ◽

Energy Homeostasis ◽

Cellular Proliferation ◽

Current Knowledge ◽

Signaling Cascades ◽

Cellular Redox ◽

Transsulfuration Pathway ◽

One Carbon Metabolism ◽

Folate Cycle

One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

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Parental Selenium Nutrition Affects the One-Carbon Metabolism and the Hepatic DNA Methylation Pattern of Rainbow Trout (Oncorhynchus mykiss) in the Progeny

Life ◽

10.3390/life10080121 ◽

2020 ◽

Vol 10 (8) ◽

pp. 121 ◽

Cited By ~ 1

Author(s):

Pauline Wischhusen ◽

Takaya Saito ◽

Cécile Heraud ◽

Sadasivam J. Kaushik ◽

Benoit Fauconneau ◽

...

Keyword(s):

Dna Methylation ◽

Rainbow Trout ◽

Carbon Metabolism ◽

Methylation Pattern ◽

Mrna Levels ◽

Transsulfuration Pathway ◽

Methionine Cycle ◽

Dna Methylation Pattern ◽

One Carbon Metabolism ◽

The One

Selenium is an essential micronutrient and its metabolism is closely linked to the methionine cycle and transsulfuration pathway. The present study evaluated the effect of two different selenium supplements in the diet of rainbow trout (Onchorhynchus mykiss) broodstock on the one-carbon metabolism and the hepatic DNA methylation pattern in the progeny. Offspring of three parental groups of rainbow trout, fed either a control diet (NC, basal Se level: 0.3 mg/kg) or a diet supplemented with sodium selenite (SS, 0.8 mg Se/kg) or hydroxy-selenomethionine (SO, 0.7 mg Se/kg), were collected at swim-up fry stage. Our findings suggest that parental selenium nutrition impacted the methionine cycle with lower free methionine and S-adenosylmethionine (SAM) and higher methionine synthase (mtr) mRNA levels in both selenium-supplemented treatments. DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) identified differentially methylated cytosines (DMCs) in offspring livers. These DMCs were related to 6535 differentially methylated genes in SS:NC, 6890 in SO:NC and 7428 in SO:SS, respectively. Genes with the highest methylation difference relate, among others, to the neuronal or signal transmitting and immune system which represent potential targets for future studies.

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Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00345.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. E61-E67 ◽

Cited By ~ 25

Author(s):

Simon G. Lamarre ◽

Anne M. Molloy ◽

Stacey N. Reinke ◽

Brian D. Sykes ◽

Margaret E. Brosnan ◽

...

Keyword(s):

Carbon Metabolism ◽

Folate Metabolism ◽

Methionine Synthase ◽

Vitamin B ◽

Metabolomic Analysis ◽

Elevated Plasma ◽

H Nmr ◽

Transsulfuration Pathway ◽

One Carbon Metabolism ◽

The One

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 301: E000–E000, 2011. First published September 20, 2011; 10.1152/ajpendo.00345.2011.—We carried out a1H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 μM in control rats to 402 μM in vitamin B12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12- and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine β-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways.

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The Prevalence of Anti-Zein Antibodies: A Comparative Study between Celiac Disease and Irritable Bowel Syndrome

Nutrients ◽

10.3390/nu13020649 ◽

2021 ◽

Vol 13 (2) ◽

pp. 649

Author(s):

Luis Alberto Sánchez-Vargas ◽

Karina Guadalupe Hernández-Flores ◽

Francisco Javier Cabrera-Jorge ◽

José María Remes-Troche ◽

Job Reyes-Huerta ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Celiac Disease ◽

Gastrointestinal Disorder ◽

Newly Diagnosed ◽

Disease Group ◽

Immune Mediated ◽

Healthy Control ◽

Gliadin Peptides ◽

Irritable Bowel ◽

First Time

Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals. In contrast, irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder affecting the large intestine, without an autoimmune component. Here, we evaluated the prevalence of IgA and IgG antibodies to maize zeins (AZA) in patients with CD and IBS. Using an in-house ELISA assay, the IgA and IgG anti-zein antibodies in the serum of 37 newly diagnosed CD (16 biopsy proved and 21 serological diagnosis) and 375 IBS patients or 302 healthy control (HC) subjects were measured. Elevated levels of IgA AZA were found in CD patients compared with IBS patients (p < 0.01) and HC (p < 0.05). CD patients had the highest prevalence (35.1%), followed by IBS (4.3%) and HCs (2.3%) (p < 0.0001). IgG AZA antibodies were not found in any CD patients, IBS patients, or HC subjects. A significant positive correlation was found between IgA AZA with IgA anti-gliadin (AGA, r = 0.34, p < 0.01) and IgA anti-deaminated gliadin peptides (DGP, r = 0.42, p < 0.001) in the celiac disease group. Taken together, our results show for the first time a higher prevalence of AZA IgA antibodies in newly diagnosed CD patients than in IBS patients, confirming a biased immune response to other gliadin-related prolamins such as maize zeins in genetically susceptible individuals.

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Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study

Nutrients ◽

10.3390/nu12020580 ◽

2020 ◽

Vol 12 (2) ◽

pp. 580

Author(s):

Camilo G. Sotomayor ◽

Isidor Minović ◽

Manfred L. Eggersdorfer ◽

Ineke J. Riphagen ◽

Martin H. de Borst ◽

...

Keyword(s):

Vitamin E ◽

Carbon Metabolism ◽

Serum Vitamin ◽

Elderly Subjects ◽

Vitamin Supplement ◽

Total Lipids ◽

Metabolism Pathway ◽

Age Related ◽

One Carbon Metabolism ◽

The One

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

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Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015129 ◽

2020 ◽

Vol 295 (47) ◽

pp. 16037-16057 ◽

Cited By ~ 1

Author(s):

Muskan Bhatia ◽

Jyotika Thakur ◽

Shradha Suyal ◽

Ruchika Oniel ◽

Rahul Chakraborty ◽

...

Keyword(s):

Carbon Metabolism ◽

Methylenetetrahydrofolate Reductase ◽

Isotope Labeling ◽

Redox Homeostasis ◽

Regulatory Region ◽

Regulatory Control ◽

Growth Defect ◽

Transsulfuration Pathway ◽

One Carbon Metabolism ◽

The Impact

Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.

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Maternal vitamin D deficiency impact on LCPUFA and pregnancy outcome associated with alterations in the one carbon metabolism

Nutrition Research ◽

10.1016/j.nutres.2020.11.009 ◽

2020 ◽

Author(s):

Anindita A. Nandi ◽

Nisha S. Wadhwani ◽

Karuna N. Randhir ◽

Shweta D. Madiwale ◽

Juilee S. Deshpande ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Pregnancy Outcome ◽

Carbon Metabolism ◽

Maternal Vitamin ◽

One Carbon Metabolism ◽

The One

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Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

Oncology ◽

10.1159/000509658 ◽

2020 ◽

Vol 98 (12) ◽

pp. 897-904

Author(s):

Sook Kyung Do ◽

Sun Ha Choi ◽

Shin Yup Lee ◽

Jin Eun Choi ◽

Hyo-Gyoung Kang ◽

...

Keyword(s):

Lung Cancer ◽

Carbon Metabolism ◽

Genetic Variants ◽

Early Stage ◽

Small Cell ◽

Survival Outcomes ◽

Small Cell Lung ◽

Metabolism Pathway ◽

One Carbon Metabolism ◽

The One

Background: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). Methods: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. Results: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, p = 0.03, respectively). Conclusions: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

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