Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice

Background  Betaine serves as a methyl donor in a reaction converting homocysteine to methionine. It is commonly used for the treatment of hyperhomocysteinemia in humans, which indicates it may be associated with reduced risk of atherosclerosis. However, there have been few data regarding its vascular effect. Aim of the study  To investigate the effect of betaine supplementation on atherosclerotic lesion in apolipoprotein (apo) E-deficient mice. Methods  Four groups of apoE-deficient mice were fed AIN-93G diets supplemented with 0, 1, 2, or 4 g betaine/100 g diet (no, 1, 2, and 4% betaine, respectively). Wild-type C57BL/6 J mice were fed AIN-93G diet (wild-type). Mice were sacrificed after 0, 7, or 14 weeks of the experimental diets. Atherosclerotic lesion area in the aortic sinus, levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 in aorta and serum, serum lipids, and methylation status of TNF-α promoter in aorta were determined. Results  Linear regression analysis showed that the higher dose of betaine was related to smaller atherosclerotic lesion area (β = −11.834, P < 0.001). Compared with no-betaine mice after 14 weeks, mice receiving 1%, 2%, or 4% betaine had 10.8, 41, and 37% smaller lesion area, respectively. Betaine supplementation also reduced aortic expression of TNF-α in a dose-dependent way in four groups of apoE-deficient mice, and Pearson correlation revealed that atherosclerotic lesion area was positively associated with aortic TNF-α level (r = 0.777, P < 0.001). Although serum TNF-α levels were lower in betaine-supplemented mice than in no-betaine mice after fourteen weeks of treatment (P < 0.001), we did not observe a significant dosage effect (P = 0.11). However, methylation level of TNF-α promoter did not differ among groups at any time. In this study, apoE-deficient mice receiving betaine supplementation for 14 weeks had higher concentrations of serum total cholesterol (P < 0.01), LDL cholesterol (P < 0.05), and lower body weight (P < 0.05) than no-betaine mice. Conclusions  These data suggest that despite exacerbating hyperlipidemia in apoE-deficient mice, betaine may exert its anti-atherogenic effect by inhibiting aortic inflammatory response mediated by TNF-α.