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      Plasma Lipids and Betaine Are Related in an Acute Coronary Syndrome Cohort

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          Abstract

          Background

          Low plasma betaine has been associated with unfavorable plasma lipid profiles and cardiovascular risk. In some studies raised plasma betaine after supplementation is associated with elevations in plasma lipids. We aimed to measure the relationships between plasma and urine betaine and plasma lipids, and the effects of lipid-lowering drugs on these.

          Methodology

          Fasting plasma samples were collected from 531 subjects (and urine samples from 415) 4 months after hospitalization for an acute coronary syndrome episode. In this cross-sectional study, plasma betaine and dimethylglycine concentrations and urine excretions were compared with plasma lipid concentrations. Subgroup comparisons were made for gender, with and without diabetes mellitus, and for drug treatment.

          Principal Findings

          Plasma betaine negatively correlated with triglyceride (Spearman's r s  = −0.22, p<0.0001) and non-high-density lipoprotein cholesterol ( r s  = −0.27, p<0.0001). Plasma betaine was a predictor of BMI (p<0.05) and plasma non-high-density lipoprotein cholesterol and triglyceride (p<0.001) independently of gender, age and the presence of diabetes. Using data grouped by plasma betaine decile, increasing plasma betaine was linearly related to decreases in BMI (p = 0.008) and plasma non-HDL cholesterol (p = 0.002). In a non-linear relationship betaine was negatively associated with elevated plasma triglycerides (p = 0.004) only for plasma betaine >45 µmol/L. Subjects taking statins had higher plasma betaine concentrations (p<0.001). Subjects treated with a fibrate had lower plasma betaine (p = 0.003) possibly caused by elevated urine betaine loss (p<0.001). The ratio of coenzyme Q to non-high-density lipoprotein cholesterol was higher in subjects with higher plasma betaine, and in subjects taking a statin.

          Conclusion

          Low plasma betaine concentrations correlated with an unfavourable lipid profile. Betaine deficiency may be common in the study population. Controlled clinical trials of betaine supplementation should be conducted in appropriate populations to determine whether correction affects cardiovascular risk.

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          Most cited references48

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          Choline and betaine in health and disease.

          Per Ueland (2011)
          Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine-homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B₂, B₆, and B₁₂) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.
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            The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism.

            Betaine is an essential osmolyte and source of methyl groups and comes from either the diet or by the oxidation of choline. Its metabolism methylates homocysteine to methionine, also producing N,N-dimethylglycine. Betaine insufficiency is associated with the metabolic syndrome, lipid disorders and diabetes, and may have a role in vascular and other diseases. Betaine is important in development, from the pre-implantation embryo to infancy. Betaine supplementation improves animal and poultry health, but the effect of long-term supplementation on humans is not known, though reports that it improves athletic performance will stimulate further studies. Subsets of the population that may benefit from betaine supplementation could be identified by the laboratory, in particular those who excessively lose betaine through the urine. Plasma betaine is highly individual, in women typically 20-60 micromol/L and in men 25-75 micromol/L. Plasma dimethylglycine is typically <10 micromol/L. Urine betaine excretion is minimal, even following a large betaine dose. It is constant, highly individual and normally <35 mmol/mole creatinine. The preferred method of betaine measurement is by LC-MS/MS, which is rapid and capable of automation. Slower HPLC methods give comparable results. Proton NMR spectrometry is another option but caution is needed to avoid confusion with trimethylamine-N-oxide. 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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              Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women.

              Choline is involved in the synthesis of phospholipids, including blood lipids, and is the immediate precursor of betaine, which serves as a methyl group donor in a reaction converting homocysteine to methionine. Several cardiovascular risk factors are associated with plasma homocysteine, whereas little is known about their relationship to choline and betaine. We examined the relation of plasma choline and betaine to smoking, physical activity, BMI, percent body fat, waist circumference, blood pressure, serum lipids, and glucose in a population-based study of 7074 men and women aged 47-49 and 71-74 y. Overall plasma concentrations (means +/- SD) were 9.9 +/- 2.3 micromol/L for choline and 39.5 +/- 12.5 micromol/L for betaine. Choline and betaine were lower in women than in men and in younger subjects compared with older (P < 0.0001). Multivariate analyses showed that choline was positively associated with serum triglycerides, glucose, BMI, percent body fat, waist circumference (P < 0.0001 for all), and physical activity (P < 0.05) and inversely related to HDL cholesterol (P < 0.05) and smoking (P < 0.0001). Betaine was inversely associated with serum non-HDL cholesterol, triglycerides, BMI, percent body fat, waist circumference, systolic and diastolic blood pressure (P < 0.0001 for all), and smoking (P < 0.05) and positively associated with HDL cholesterol (P < 0.01) and physical activity (P < 0.0001). Thus, an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations. Choline and betaine were associated in opposite directions with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline dehydrogenase pathway.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                1 July 2011
                : 6
                : 7
                : e21666
                Affiliations
                [1 ]Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand
                [2 ]Pathology Department, University of Otago, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand
                [3 ]Department of Medicine, University of Otago, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand
                Paris Institute of Technology for Life, Food and Environmental Sciences, France
                Author notes

                Conceived and designed the experiments: AMR STC SS PMG ML. Performed the experiments: WA JLE SLM SS. Analyzed the data: ML SS SLM JLE. Contributed reagents/materials/analysis tools: WA JLE SLM ML AMR. Wrote the paper: ML SS AMR STC PMG JLE SLM. Designed parent study: AMR.

                Article
                PONE-D-11-02264
                10.1371/journal.pone.0021666
                3128609
                21747945
                aa1870e3-68ee-45a4-9e87-c12de1ca7c3d
                Lever et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 27 January 2011
                : 7 June 2011
                Page count
                Pages: 9
                Categories
                Research Article
                Agriculture
                Animal Management
                Animal Nutrition
                Biology
                Biochemistry
                Lipids
                Small Molecules
                Chemistry
                Chemical Biology
                Medicine
                Cardiovascular
                Atherosclerosis
                Cardiovascular Pharmacology
                Coronary Artery Disease
                Heart Failure
                Vascular Biology
                Nutrition
                Micronutrient Deficiencies
                Obesity

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                Uncategorized

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