Sex differences in hepatic one-carbon metabolism

Sadre-Marandi, Farrah; Dahdoul, Thabat; Reed, Michael C.; Nijhout, H. Frederik

doi:10.1186/s12918-018-0621-7

Cited by 50 publications

(55 citation statements)

References 69 publications

(96 reference statements)

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“…Hence, our study raises the need to adjust choline supplementation by sex, and, possibly, age. In this regard, to understand the origin and consequences of sex differences in C1-metabolism which might be important for precision medicine, Sadre-Marandi et al created a mathematical model of hepatic C1-metabolism based on physiological and biochemical female/male ratios of enzymes and metabolites of this pathway 93 . The model might be helpful in the potential application of choline supplementation, in general, and in females, in particular.…”

Section: Discussionmentioning

confidence: 99%

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

et al. 2020

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Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/− genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/− mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/− mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

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Section: Discussionmentioning

confidence: 99%

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

et al. 2020

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“…Nevertheless, unexplained variability can be ascribed to kidney disease, explaining a positive association between Hcy and serum creatinine [5,[16][17][18][19]. It is worth noting that men with higher muscle mass have been shown to have higher levels of both Hcy and creatinine, particularly when compared to women, given that~70% of daily SAM-dependent methylation reactions are to produce creatine [20,21]. Hcy has been positively associated with red cell distribution width (RDW) [22]; with increased serum cotinine, a measure of active or passive recent smoking [23]; and with increased liver enzyme levels [24,25].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Hematological Correlates of Elevated Homocysteine in National Surveys and a Longitudinal Study of Urban Adults

Beydoun¹,

Beydoun

MacIver

et al. 2020

Nutrients

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Elevated blood homocysteine (Hcy) among middle-aged adults can increase age-related disease risk, possibly through other biochemical and hematological markers. We selected markers for hyperhomocysteinemia among middle-aged adults, studied time-dependent Hcy-marker associations and computed highly predictive indices of hyperhomocysteinemia, with cross-sectional and longitudinal validations. We used data from the National Health and Nutrition Examination Survey (NHANES III, phase 2, nmax = 4000), the NHANES 1999–2006 (nmax = 10,151) and pooled NHANES (cross-sectional validation). Longitudinal validation consisted of mixed-effects linear regression models (Hcy predicting markers’ annual rates of change), applied to the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS, n = 227–244 participants, k = 2.4 repeats/participant, Agebase: 30–65 years) data. Machine learning detected nine independent markers for Hcy > 14 µmol/L (NHANES III, phase 2): older age; lower folate and B-12 status; higher serum levels of creatinine, uric acid, alkaline phosphatase, and cotinine; mean cell hemoglobin and red cell distribution widths (RDW); results replicated in the 1999–2006 NHANES [AUC = 0.60–0.80]. Indices combining binary markers increased elevated Hcy odds by 6.9–7.5-fold. In HANDLS, first-visit Hcy predicted annual increase in creatinine, RDW and alkaline phosphatase, with third-visit index (2013–2018) directly predicting Hcy (2004–2009). We provide evidence of the internal and external validity of indices composed of several biomarkers that are strongly associated with elevated Hcy.

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“…For the effect of the intervention on CVD and heart failure/cardiac valve disease, the risks were higher in women compared to men, however, the differences were not significant. A possible greater vulnerability of women to folic acid and vitamineB12 supplementation could be explained by the influences of sex hormones in one-carbon metabolism and the differences between men and women in the expression level of enzymes in this metabolism [32].There is a gap in the knowledge of CVD in different sex and age groups, due to under-representation of women and the older population (because of higher comorbidities) [33]. It has been suggested that there is more variability of the increased risk factors by ageing, related to sex differences that could change between middle-aged and elderly adults [33].…”

Section: Discussionmentioning

confidence: 99%

Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial

et al. 2021

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Background & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5e7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebocontrolled trial designed to assess the effect of 2e3 years daily supplementation with folic acid (400 mg) and vitamin-B12 (500 mg) versus placebo (n ¼ 2,919). Primary outcome was verified selfreported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. Results: A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51e58], (n ¼ 662 and n ¼ 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0e76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62e1.59 and HR: 0.77; 95% CI: 0.50 e1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80e1.44 and OR: 0.85; 95%CI: 0.50e1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic-and any fracture (p ¼ 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 mmol/l). No age-dependent effects were present.Conclusions: This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be

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Sex differences in hepatic one-carbon metabolism

Cited by 50 publications

References 69 publications

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

Biochemical and Hematological Correlates of Elevated Homocysteine in National Surveys and a Longitudinal Study of Urban Adults

Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial

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