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Background The association of moderate hyperhomocysteinemia (HHcy) (15–30 μmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy. Objective We sought to evaluate the association of intermediate (30–100 μmol/L) and severe (>100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes. Methods We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing. Results We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 μmol/L, 27% Hcy >50 μmol/L (44/165) and 3% Hcy >100 μmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6–60.4 compared with 12.1–28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up. Conclusion The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes. [ABSTRACT FROM AUTHOR]

Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy. • Somatic mutations, epigenetic silencing and altered gene expression can produce methionine dependency. • Cancer stem cells from lung cancer and glioblastoma are methionine dependent through mirrored mechanisms. • The methionine dependency of glioblastoma stem cells can be rescued by folate. [ABSTRACT FROM AUTHOR]

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule‐associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19‐7 neuroprogenitors lacking folate. Compared with controls, N‐homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N‐homocysteinylation dissociated tau and MAPs from β‐tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β‐tubulin. N‐homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days‐old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy–thiolactone, the substrate of N‐homocysteinylation. Experimental inactivation of MARS prevented the N‐homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β‐tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N‐homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Folate plays a key role in the interactions between nutrition, fetal programming, and epigenomics. Maternal folate status influences DNA methylation, inheritance of the agouti phenotype, expression of imprinting genes, and the effects of mycotoxin FB1 on heterochromatin assembly in rodent offspring. Deficiency in folate and other methyl donors increases birth defects and produces visceral manifestations of fetal programming, including liver and heart steatosis, through imbalanced methylation and acetylation of PGC1-α and decreased SIRT1 expression, and produces persistent cognitive and learning disabilities through impaired plasticity and hippocampal atrophy. Maternal folate supplementation also produces long-term epigenomic effects in offspring, some beneficial and others negative. Deciphering these mechanisms will help understanding the discordances between experimental models and population studies of folate deficiency and supplementation. [Copyright &y& Elsevier]

Background: Association of thyroid dysfunction with plasma homocysteine levels and vitamin B12 has previously been reported. We evaluated these associations in the elderly in San Teodoro, a mountainous village of Sicily. Methods: Subjects (n=279) aged 60–85 years (119 males and 160 females) were examined using self-reported signs, clinical examination and laboratory tests. Results: Hypothyroidism and/or goiter were two characteristics that were not associated with a significant change in homocysteine when compared with euthyroidism and the absence of goiter. Vitamin B12 was significantly higher in subjects in the first quartile of the thyroid-stimulating hormone distribution, compared with those in the fourth quartile (371±207 vs. 297±196 pmol/L, p=0.0121). Homocysteine was significantly higher in the first quartile of the free tri-iodothyronine distribution compared to the third quartile (18.0±5.7 vs. 16.0±6.2 μmol/L, p=0.0130) and was correlated with log tri-iodothyronine in euthyroid subjects (p=0.0254). In multivariate analysis, homocysteine was associated with vitamin B12 (p=0.0014), folate (p<0.0001), creatinine (p<0.0001) and age (p<0.0001), but not with either free tri-iodothyronine (p=0.7680), tetra-iodothyronine (p=0.5706) or thyroid-stimulating hormone (p=0.2294). Conclusions: Our results suggest that the influence of thyroid hormones on homocysteine is much weaker in elderly subjects than in selected patients with hypothyroidism. Clin Chem Lab Med 2007;45:143–7. [ABSTRACT FROM AUTHOR]

Background: Homocysteine is associated with age, folate and vitamin B12. Our study investigated the functional and clinical characteristics of the elderly (aged 60–85 years) of San Teodoro, a village in Central Sicily, and evaluated associations with vitamin B12, folate and homocysteine. Methods: Subjects (n=280) were examined after door-to-door recruitment using interview, physician examination and laboratory tests. Results: A total of 19.3% of the population had a low blood level of folate (<7 nmol/L) and 3.2% had low vitamin B12 concentration (<100 pmol/L). The level of dependency, determined by the Barthel index, influenced homocysteine blood levels (p<0.0001), independent of age (p<0.0001), folate (p=0.0028) and vitamin B12 (p=0.0165). Homocysteine was significantly associated with stroke (p=0.0027) and peripheral arterial vascular disease (p=0.0001), but not with myocardial infarction, angina pectoris, venous thrombosis or cancer. Vitamin B12 was lower in myocardial infarction and higher in diabetes and venous thrombosis compared to the other diseases. Conclusions: The prevalence of deficits in folate and vitamin B12 was paradoxically high in the mountainous northeastern area of Sicily. Our study also underlines the association of homocysteine with dependency of the elderly and with stroke and peripheral arteriopathy. Clin Chem Lab Med 2007;45:136–42. [ABSTRACT FROM AUTHOR]

Background: Methylenetetrahydrofolate reductase (MTHFR) 677C3T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A→C is less well known. It has been hypothesized that 677T frequency could result in part from genenutrient interactions. Objective: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. Design: Healthy young adults (n=1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. Results: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R=0.976; 95% CI: 0.797, 0.996; P = 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). Conclusion: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C3T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied. [ABSTRACT FROM AUTHOR]

Background: Moderate hyperhomocysteinemia is a risk for neural tube defect and neurodegenerative and vascular diseases and has nutritional, metabolic, and genetic determinants. Its prevalence in sub-Saharan Africa remains unknown. Objective: Our goal was to evaluate the prevalence of hyperhomocysteinemia and the influence of nutritional, metabolic, and genetic determinants in savanna and coastal regions of Togo and Benin. Design: Volunteers were recruited from coastal (C groups; n=208) and savanna (S group; n = 68) regions. Vitamin B-12, folate, total homocysteine (tHcy), cystatin C (a marker of glomerular filtration), and inflammatory and nutritional protein markers were measured in plasma, and the methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C polymorphisms and the methionine synthase 2756A→G polymorphism were examined in genomic DNA. Results: Moderate hyperhomocysteinemia (tHcy > 15 μmol/L) was recorded in 62.3% and 29.4% of the subjects from the coast and savanna, respectively (P < 0.0001). A histogram distribution of tHcy in the coastal groups showed a distinct group, C2 (15% of the total group), with tHcy > 28 μmol/L. Folate < 6.75 nmol/L (lower quartile) and MTHFR CT/TT genotype were the 2 main risk factors for moderate hyperhomocysteinemia in the whole population [odds ratios: 5.3 (95% CI: 2.5, 11.2; P = 0.0001) and 4.9 (1.6, 14.8; P = 0.0048), respectively] and in the C2 group [odds ratios: 15.9 (4.5, 56.8; P = 0.0001) and 9.0 (2.3, -35.2; P = 0.0017), respectively]. Cystatin C was another potent risk factor in the C2 group. Conclusion:Ahigh prevalence of hyperhomocysteinemia in coastal West Africa, related to folate concentrations and the MTHFR 677 T allele, suggests the need to evaluate the influence of hyperhomocysteinemia on disease in this area. Am J Clin Nutr 2004;79: 619-24. [ABSTRACT FROM AUTHOR]

One-carbon metabolism is under the influence of folate, vitamin B[sub12] and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C→T and 1298 A→C), of methionine synthase (MTR 2756 C→G), methionine synthase reductase (MTRR 66 C→G) and transcobalamin (TCN 776 C →G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C→T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B[sub12], increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C→T and MTRR 66 A→G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C→T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations. [ABSTRACT FROM AUTHOR]

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation. [ABSTRACT FROM AUTHOR]

Homocysteine (Hcy) is a non-protein forming amino acid which is the direct metabolic precursor of methionine. Increased concentration of serum Hcy is considered a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature. Serum Hcy is associated with atherosclerosis, hypertension and aneurysms of the aorta in humans, though the precise mechanisms by which Hcy contributes to these conditions remain elusive. Results from clinical trials that successfully lowered serum Hcy without reducing features of vascular disease in cardiovascular patients have cast doubt on whether or not Hcy directly impacts the vasculature. However, studies in animals and in cell culture suggest that Hcy has a vast array of toxic effects on the vasculature, with demonstrated roles in endothelial dysfunction, medial remodeling and adventitial inflammation. It is hypothesized that rather than serum Hcy, tissue-bound Hcy and the incorporation of Hcy into proteins could underlie the toxic effects of Hcy on the vasculature. In this review, we present evidence for Hcy-associated vascular disease in humans, and we critically examine the possible mechanisms by which Hcy specifically impacts the endothelial, medial and adventitial layers of the arterial wall. Deciphering the mechanisms by which Hcy interacts with proteins in the arterial wall will allow for a better understanding of the pathomechanisms of hyperhomocysteinemia and will help to define a better means of prevention at the appropriate window of life. [ABSTRACT FROM AUTHOR]

Homocysteine (HCY) is a degradation product of the methionine pathway. The B vitamins, in particular vitamin B12 and folate, are the primary nutritional determinant of HCY levels and therefore their deficiencies result in hyperhomocysteinaemia (HHCY). Prevalence of hyperhomocysteinemia (HHCY) and related dietary deficiencies in B vitamins and folate increase with age and have been related to osteoporosis and abnormal development of epiphyseal cartilage and bone in rodents. Here we provide a review of experimental and population studies. The negative effects of HHCY and/or B vitamins and folate deficiencies on bone formation and remodeling are documented by cell models, including primary osteoblasts, osteoclast and bone progenitor cells as well as by animal and human studies. However, underlying pathophysiological mechanisms are complex and remain poorly understood. Whether these associations are the direct consequences of impaired one carbon metabolism is not clarified and more studies are still needed to translate these findings to human population. To date, the evidence is limited and somewhat conflicting, however further trials in groups most vulnerable to impaired one carbon metabolism are required. [ABSTRACT FROM AUTHOR]

MTHFD1 is a trifunctional protein containing 10-formyltetrahydrofolate synthetase, 5,10-methenyltetrahydrofolate cyclohydrolase and 5,10-methylenetetrahydrofolate dehydrogenase activities. It is encoded by MTHFD1 and functions in the cytoplasmic folate cycle where it is involved in de novo purine synthesis, synthesis of thymidylate and remethylation of homocysteine to methionine. Since the first reported case of severe combined immunodeficiency resulting from MTHFD1 mutations, seven additional patients ascertained through molecular analysis have been reported with variable phenotypes, including megaloblastic anemia, atypical hemolytic uremic syndrome, hyperhomocysteinemia, microangiopathy, infections and autoimmune diseases. We determined the level of MTHFD1 expression and dehydrogenase specific activity in cell extracts from cultured fibroblasts of three previously reported patients, as well as a patient with megaloblastic anemia and recurrent infections with compound heterozygous MTHFD1 variants that were predicted to be deleterious. MTHFD1 protein expression determined by Western blotting in fibroblast extracts from three of the patients was markedly decreased compared to expression in wild type cells (between 4.8 and 14.3% of mean control values). MTHFD1 expression in the fourth patient was approximately 44% of mean control values. There was no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts from any of the four patients. This is the first measurement of MTHFD1 function in MTHFD1 deficient patients and confirms the previous molecular diagnoses. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily. Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (−2.78 vs. −0.4 points) and (−1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed. This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children. • Folinic acid treatment is well tolerated in children with Autism spectrum disorders. • Folinic acid treatment shows improvement in Autism Diagnostic Observation Schedule score. • Effect of 10 mg/d folinic acid should be confirmed by a larger a multi-center trial. [ABSTRACT FROM AUTHOR]

Deficiency in methyl donor (folate and vitamin B12) and in vitamin D is independently associated with altered bone development. Previously, methyl donor deficiency (MDD) was shown to weaken the activity of nuclear receptor coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), for nuclear signaling in rat pups, including estrogen receptor-α and estrogen-related receptor-α; its effect on vitamin D receptor (VDR) signaling, however, is unknown. We studied bone development under MDD in rat pups and used human MG-63 preosteoblast cells to better understand the associated molecular mechanism. In young rats, MDD decreased total body bone mineral density, reduced tibia length, and impaired growth plate maturation, and in preosteoblasts, MDD slowed cellular proliferation. Mechanistic studies revealed decreased expression of VDR, estrogen receptor-α, PGC1α, arginine methyltransferase 1, and sirtuin 1 in both rat proximal diaphysis of femur and in MG-63, as well as decreased nuclear VDR-PGC1α interaction in MG-63 cells. The weaker VDR-PGC1α interaction could be attributed to the reduced protein expression, imbalanced PGC1α methylation/acetylation, and nuclear VDR sequestration by heat shock protein 90 (HSP90). These together compromised bone development, which is reflected by lowered bone alkaline phosphatase and increased proadipogenic peroxisome proliferator-activated receptor-γ, adiponectin, and estrogen-related receptor-α expression. Of interest, under MDD, the bone development effects of 1,25-dihydroxyvitamin D3 were ineffectual and these could be rescued by the addition of S-adenosylmethionine, which restored expression of arginine methyltransferase 1, PGC1α, adiponectin, and HSP90. In conclusion, MDD inactivates vitamin D signaling via both disruption of VDR-PGC1α interaction and sequestration of nuclear VDR attributable to HSP90 overexpression. These data suggest that vitamin D treatment may be ineffective under MDD. [ABSTRACT FROM AUTHOR]

Vitamin B 12 and folate are essential micronutrients that provide methyl groups for cellular methylations through the so-called one-carbon metabolism. Deficits in the absorption and transport or defects of the enzymes can lead to human pathogenesis comprising hematologic, neural, gastrointestinal, hepatic, renal, cardiovascular and developmental manifestations. One-carbon metabolism is a complex, multistep and multi-organ metabolism, and the understanding of the mechanisms at work have benefited from human inborn errors and population studies, as well as from nutritional animal models. Since 15 years, a wide variety of genetically engineered mice has been developed and has proved to be useful to decipher the underlying mechanisms. These genetically engineered mice target all the genes that are important for the intestinal absorption, cellular transport and metabolism of vitamin B 12 and folate, which are detailed in this article. In conclusion, these mouse models represent valuable experimental paradigms for human pathogenesis. Since no animal model recapitulates the full spectrum of a human disease, researchers have to choose the one that is the most relevant for their specific needs, and this review may help in this respect. [ABSTRACT FROM AUTHOR]

Background & Aims: Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown. Methods: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. Results: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl–palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-l-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-α, ERR-α and HNF-4α, and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α, and HNF-4α. Conclusions: The liver steatosis resulted predominantly from hypomethylation of PGC1-α, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis. [Copyright &y& Elsevier]

Abstract: Objective: The ankle brachial index (ABI) is an indicator of lower extremity peripheral arterial disease (PAD) and a predictor of atherothrombosis. ApoA-I and HDL are associated with PAD, in humans. Homocysteine influences the liver expression of ApoA-I and decreases its blood level and HDL in genetic mice models. We aimed therefore to evaluate whether homocysteine and its nutritional determinants, folate and vitamin B12 are associated with ABI by influencing HDL metabolism, in an ambulatory elderly population. Methods: 667 elderly volunteers from rural Sicily were assessed for ABI, homocysteine and its determinants, lipid markers and other predictors of PAD. HDL size was assessed in 15 sera in upper and lower quartiles of Hcy distribution. Results: In multivariate analysis, ApoA-I and homocysteine were two predictors of ABI (β-coefficient=2.86, P <0.004 and β-coefficient=−3.41, P <0.001, respectively). Homocysteine correlated negatively with ApoA-I (R =−0.147, P <0.001) and with HDL-Cholesterol (R =−0.113, P =0.003). The associations of homocysteine, vitamin B12 and methylmalonic acid with ApoA-I and HDL2a particles and that of homocysteine with increased small size HDL3c suggested mechanisms related with impaired synthesis of ApoA-I and HDL and abnormal maturation of HDL particles. Conclusion: The influence of homocysteine on ApoA-I and HDL metabolism provides new insights on its role on vascular diseases, at a cross-point between atherosclerosis and atherothrombosis. [Copyright &y& Elsevier]

Abstract: The integrated view of the expression of genes involved in folate-dependent one-carbon metabolism (FOCM) under folate deficiency remains unknown. Dynamics of changes in the transcriptional expression of 28 genes involved in the FOCM network were evaluated at different time points (0, 2, 4, 6, 12, 24 and 48 h) in human hepatoma HepG2 cell line. Combined experimental and computational approaches were conducted for emphasizing characteristic patterns in the gene expression changes produced by cellular folate deficiency. Bivariate analysis showed that folate deficiency (0.3 nmol/L of folate vs. 2.27 μmol/L in control medium) displayed rapid and coordinated regulation during the first 2 h with differential expression for hRfc1 (increased by 69%) and Ahcy (decreased by 437%). Density analysis through the time points gave evidence of differential expression for five genes (Ahcy, Cth, Gnmt, Mat1A, Mtrr and hRfc1). Differential expression of Ahcy, Gnmt, Mat1A and Mtrr was confirmed by time-series analysis gene expression. We also found a marked differential expression of Mtrr. Qualitative analysis of genes allowed identifying four clusters of gene that was coexpressed. Two of these clusters were consistent with specific metabolic functions as they associated genes involved in the remethylation (Mthfr and Mtrr) and in the transmethylation (Dnmt1and Dnmt3B) pathways. The study shows a strong influence of folate status on Mtrr transcription in HepG2 cells. It suggests also that folate deficiency produces transcription changes that particularly involve the clusters of genes related with the remethylation and the transmethylation pathways. [Copyright &y& Elsevier]

Background/Aims: Homocysteine metabolism is linked to DNA methylation, a mechanism potentially involved in the course of hepatitis B virus (HBV) infection. We evaluated the association of determinants of homocysteine metabolism with the outcome of HBV infection. Methods: Four hundred and fifty-five healthy adults from Togo and Benin were tested for HBV serologic markers, HLA DR alleles, folate, vitamin B12, methylenetetrahydrofolate reductase (MTHFR) 677 C→T, 1298 A→C and methionine synthase 2756 A→G polymorphisms. Results: Seventy-eight percent of the study population was anti-HBc positive. Among them, 202 (56.9%) were anti-HBs positive and 58 (16.3%) were HBsAg positive. After stepwise logistic regression, the MTHFR 677 T allele was independently associated with persistence of detectable anti-HBs antibodies (OR: 2.47; 95% CI: 1.29–4.71; p =0.006). The mean HBV DNA level was significantly lower in HBsAg positive subjects carrying the 677 T allele than in those with the 677 CC genotype (1000±1406 vs. 2,400,000±214,000 copies/ml, p =0.005). Beninese origin and HLA-DRB1*09 allele were the other determinants independently associated with favorable outcome of HBV infection. Conclusions: The methylenetetrahydrofolate reductase 677 T allele seems to protect against chronic HBV infection in young African adults. [Copyright &y& Elsevier]

The risks of nonalcoholic steatohepatitis (NASH) and deficiency in vitamin B12 and folate (methyl donor deficiency, MDD) are increased in inflammatory bowel disease (IBD). We investigated the influence of MDD on NASH in rats with DSS-induced colitis. Two-month-old male Wistar rats were subjected to MDD diet and/or ingestion of DSS and compared to control animals. We studied steatosis, inflammation, fibrosis, plasma levels of metabolic markers, cytokines and lipopolysaccharide, and inflammatory pathways in liver. MDD triggered a severe macrovesicular steatosis with inflammation in DSS animals that was not observed in animals subjected to DSS or MDD only. The macrovesicular steatosis was closely correlated to folate, vitamin B12, homocysteine plasma level and liver S-adenosyl methionine/S-adenosyl homocysteine (SAM/SAH) ratio. Liver inflammation was evidenced by activation of nuclear factor kappa B (NFκB) pathway and nuclear translocation of NFκB phospho-p65. MDD worsened the increase of interleukin 1-beta (IL-1β) and abolished the increase of IL10 produced by DSS colitis. It increased monocyte chemoattractant protein 1 (MCP-1). MDD triggers liver macrovesicular steatosis and inflammation through imbalanced expression of IL-1β vs. IL10 and increase of MCP-1 in DSS colitis. Our results suggest evaluating whether IBD patients with MDD and increase of MCP-1 are at higher risk of NASH. [ABSTRACT FROM AUTHOR]