Betaine reduces serum uric acid levels and improves kidney function in hyperuricemic mice

Betaine as a dietary alkaloid has attracted the attention of patients with kidney diseases. This study aimed to investigate the effects of betaine on serum uric acid levels and kidney function, and explore their underlying mechanisms in potassium oxonate-induced hyperuricemic mice. Betaine at 5, 10, 20, and 40 mg/kg was orally administered to hyperuricemic mice for 7 days and found to significantly reduce serum uric acid levels and increase fractional excretion of uric acid in hyperuricemic mice in a dose-dependent manner. It effectively restored renal protein level alterations of urate transport-related molecular proteins urate transporter 1, glucose transporter 9, organic anion transporter 1, and ATP-binding cassette subfamily G member 2 in this model, possibly resulting in the enhancement of kidney urate excretion. Moreover, betaine reduced serum creatinine and blood urea nitrogen levels and affected urinary levels of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase as well as upregulated renal protein levels of organic cation/carnitine transporters OCT1, OCTN1, and OCTN2, resulting in kidney function improvement in hyperuricemic mice. The findings from this study provide evidence that betaine has anti-hyperuricemic and nephroprotective actions by regulating protein levels of these renal organic ion transporters in hyperuricemic mice.

Liu, Y.L., et al., Betaine Reduces Serum Uric Acid Levels and Improves Kidney Function in Hyperuricemic Mice. Planta Med, 2013

Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high fat diet

Aberrant DNA methylation contributes to the abnormality of hepatic gene expression, one of the main factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Betaine is a methyl donor and has been considered to be a lipotropic agent. However, whether betaine supplementation improves NAFLD via its effect on the DNA methylation of specific genes and the genome has not been explored. Male C57BL/6 mice were fed either a control diet (CD) or high fat diet (HFD) supplemented with 0%, 1% and 2% betaine in water (wt/vol) for 12 weeks. Betaine supplementation ameliorated HFD-induced hepatic steatosis in a dose-dependent manner. HFD upregulated FAS and ACOX mRNA expression and downregulated PPARα, ApoB and MTTP mRNA expression; however, these alterations were reversed by betaine supplementation except ApoB. MTTP mRNA expression was negatively correlated with the DNA methylation of its CpG sites at -184, -156, -63 and -60. Methylation of these CpG sites was lower in both the 1% and 2% betaine-supplemented groups than in the HFD group (averages; 25.55% and 14.33% vs. 30.13%). In addition, both 1% and 2% betaine supplementation significantly restored the methylation capacity (SAM concentration and SAM/SAH ratios) and genomic methylation level which had been decreased by HFD (0.37% and 0.47% vs. 0.25%). These results suggest that the regulation of aberrant DNA methylation by betaine might be a possible mechanism of the improvements in NAFLD upon betaine supplementation.

Wang, L.-j., et al., Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high fat diet. The Journal of Nutritional Biochemistry, 2013

Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency

IMPORTANCE The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear.
OBJECTIVE To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012. STUDY SELECTION Studies that described patients with severe MTHFR deficiency who received betaine treatment.
DATA EXTRACTION AND SYNTHESIS We identified 15 case reports and case series, totaling 36 patients. Data included the following: (1) families with 2 or more patients with severe MTHFR deficiency, of whom at least 1 received betaine, or (2) single patients with severe MTHFR deficiency treated with betaine. To define severe MTHFR deficiency, methionine, homocysteine, MTHFR enzyme activity in fibroblasts, or mutations (in the MTHFR gene) had to be described as well as the effect of treatment (survival and/or psychomotor development). We compared the outcome in treated vs untreated patients and early- vs late-treated patients. Sensitivity analysis was performed to address definition of early treatment. To further assess the impact of treatment on mortality, we performed a subanalysis in families with at least 1 untreated deceased patient.
MAIN OUTCOMES AND MEASURES Survival and psychomotor development.
RESULTS Eleven of 36 patients (31%) died. All deaths occurred in patients who did not receive treatment or in patients in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Subgroup analysis of patients with deceased siblings-their genotypically identical controls-revealed that betaine treatment prevented mortality (P = .002). In addition, psychomotor development in surviving patients treated with betaine was normal in all 5 early-treated patients but in none of the 19 surviving patients with delayed treatment (P < .001).
CONCLUSIONS AND RELEVANCE Early betaine treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.

Diekman, E.F., et al., Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency. JAMA Neurol, 2013

Betaine alleviates hypertriglycemia and tau hyperphosphorylation in db/db mice

Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/db+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.

Jung, G.Y., et al., Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in Mice. Toxicol Res, 2013. 29(1): p. 7-14.

Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma

Background: Intakes of choline and betaine have been inversely related to the risk of various neoplasms, but scant data exist on nasopharyngeal carcinoma (NPC). We examined the association between consumption of choline and betaine and risk of NPC.

Methods: We conducted a case-control study with 600 incident NPC patients and 600 controls 1 : 1 matched by age, sex and household type in Guangdong, China. Dietary intake was assessed by a food frequency questionnaire through face-to-face interview.

Results: Intakes of total choline, betaine and choline+betaine were inversely related to NPC after adjustment for various lifestyle and dietary factors. Adjusted odds ratios (95% CI) for quartile 4 (vs quartile 1) were 0.42 (0.29, 0.61) for total choline, 0.50 (0.35, 0.72) for betaine and 0.44 (0.30, 0.64) for betaine+total choline. Regarding various sources of choline, lower NPC risk was associated with greater intakes of choline from phosphatidylcholine, free choline, glycerophosphocholine and phosphocholine, but not sphingomyelin.

Conclusion: These findings are consistent with a beneficial effect of choline and betaine intakes on carcinogenesis.

Zeng, F.F., et al., Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma in adults: a case-control study. Br J Cancer, 2013

Cereal foods are the major source of betaine in the Western diet

Betaine and its precursor choline are important components of one-carbon metabolism, remethylating homocysteine into methionine and providing methyl groups for DNA methylation. Cereals are the main source of betaine in the diet, though there is little literature available on the content of betaine in cereal products, nor on betaine intake from cereals. Betaine and free-choline concentrations were measured by liquid-chromatography with tandem mass spectrometry in a wide range of commercially available cereal foods and cereal fractions. Whole grain wheat and related fractions were the best overall common source of betaine, while the pseudocereal quinoa had the highest amount of betaine measured (3900mug/g). Based on estimates of dietary intake data cereal foods provide approximately 60-67% of betaine in Western diets, and 20-40% of betaine in South-East Asian diets. Average intake of betaine was 131mg/d, well below those used in intervention studies using betaine to lower blood homocysteine.

Ross, A.B., A. Zangger, and S.P. Guiraud, Cereal foods are the major source of betaine in the Western diet - Analysis of betaine and free choline in cereal foods and updated assessments of betaine intake. Food Chem, 2014. 145C: p. 859-865

Supplementation with B12 vitamin, betaine or other methyl donors in addition to folic acid may further reduce NTD risk

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

Imbard, A., J.F. Benoist, and H.J. Blom, Neural tube defects, folic Acid and methylation. Int J Environ Res Public Health, 2013. 10(9): p. 4352-89