Betaine prevents vasculature remodeling and inflammatory response during vascular aging

We previously reported that lysophosphatidylcholine (LPC) is a mediator of endothelial dysfunction in expression of adhesion molecules (AMs) during aging. This study aimed at investigating the effects of betaine on LPC-related expression of AMs and the molecular modulation of nuclear factor-kappaB (NF-kappaB) activation in the aorta of aged rats and rat endothelial YPEN-1 cells. The experiment was performed on young (7months) and old (21months) rats; 2 groups of old rats were fed betaine (3 or 6mg*kg-1*day-1 for 10days). Betaine inhibited the expression of LPC-related AMs in the serum and tissue of aged rats, without affecting the elevated levels of serum LPC. Betaine also prevented the generation of reactive species, thereby maintaining the redox status via the enhancement of the thiol status during aging. Furthermore, betaine attenuated NF-kappaB activation via the dephosphorylation of IkappaB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged aorta and LPC-treated YPEN-1 cells. Thus, betaine suppressed the LPC-related AM expression associated with NF-kappaB activation via the upregulation of IKK/MAPKs. Our findings provide insights into the prevention of vascular disorders and the development of interventions based on natural compounds, such as betaine.

Lee, E.K., et al., Betaine attenuates lysophosphatidylcholine-mediated adhesion molecules in aged rat aorta: Modulation of the nuclear factor-kappaB pathway. Exp Gerontol, 2013

Metabolomic study with high fat diet

This study used 1H nuclear magnetic resonance (NMR) spectroscopy to examine the metabolic profiles of plasma and urine from the low-density lipoprotein receptors (LDLR) knockout mice.

Consistent with previous studies, these mice developed hypercholesterolemia and atherosclerosis when fed a high-fat/cholesterol/cholate containing diet. In addition, multivariate statistical analysis of the metabolomic data highlighted significant differences in tricarboxylic acid cycle and fatty acid metabolism, as a result of high-fat/cholesterol diet feeding. The high-fat/cholesterol/cholate diet, LDL receptor gene deficiency, and the diet-genotype interaction caused a significant perturbation in choline metabolism, notably the choline oxidation pathway. Specifically, the loss in the LDL receptor caused a marked reduction in the urinary excretion of betaine and dimethylglycine, especially when the mice are fed a high fat/cholesterol/cholate diet.

These metabolic changes are comparable with those detected in ApoE knockout mice fed the same high-fat/cholesterol/cholate diet and may be useful for monitoring the onset of atherosclerosis across animal models.


Cheng et al (2010). "A metabolomic study of the LDL receptor null mouse fed a high-fat diet reveals profound perturbations in choline metabolism that are shared with ApoE null mice." Physiol. Genomics 41: 224-231.

Betaine is atheroprotective

Paraoxonase (PON1) is an antioxidant enzyme that prevents LDL oxidation as well as detoxifies homocysteine thiolactone (HCTL), both of which can cause atherosclerosis. Chronic alcohol (ETOH) and high ω-3 polyunsaturated fatty acids (ω-3 PUFA) consumption may affect PON1 status presumably via reactive oxygen species by depleting liver glutathione (GSH), whereas betaine may counter their effects.

Experimental rats belonging to various dietary groups were pair-fed with Lieber-DeCarli low (2.8% the dietary calories as ω3-fatty acids) and high (13.8% the dietary calories as ω3-fatty acids) menhaden fish alcohol-liquid diets with and without betaine (10 g/l diet) for 8 weeks after which liver PON1 mRNA, GSH, lipid score, and serum PON1, HCTLase, and ALT activities were measured.

Betaine restored liver PON1 mRNA expressions in low and high ω-3 PUFA ETOH groups with parallel restorations of PON1 activity and liver GSH. Concomitantly, betaine reduced hepatosteatosis accompanied by alleviation of liver injury caused by chronic alcohol and high ω-3 PUFA.

Dietary betaine was atheroprotective by restoring liver glutathione (GSH) that quenches free radicals, but also may alleviate liver injury by reducing hepatosteatosis.

Varatharajalu et al (2009). "Betaine Protects Chronic Alcohol and Omega-3 PUFA-Mediated Down-Regulations of PON1 Gene, Serum PON1 and Homocysteine Thiolactonase Activities With Restoration of Liver GSH." Alcoholism: Clinical and Experimental Research. Epub Dec 17.

Betaine reduces athersclerosis and inflammatory response

This study investigated the effect of betaine supplementation on atherosclerotic lesion in apolipoprotein (apo) E-deficient mice. Four groups of these 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.

The results showed:

- 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 reduced aortic expression of TNF-α in a dose-dependent way.
- betaine supplementation for 14 weeks led to higher concentrations of serum total cholesterol (P < 0.01), LDL cholesterol (P < 0.05), and lower body weight (P < 0.05).

The authors concluded that despite exacerbating hyperlipidemia in apoE-deficient mice, betaine may exert its anti-atherogenic effect by inhibiting aortic inflammatory response mediated by TNF-α.

Lv et al (2009). "Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice." Eur J Nutr 48(4): 205-12.

Betaine inhibits atherosclerosis via anti-inflammation

Five groups of mice were studied: ApoE-deficient (model group and three betaine groups) and wild-type mice as control. The control group and model group were fed AIN-93G diet. Three betaine groups were fed AIN-93G diet supplemented with 1, 2, 4 g betaine/100 g diet, respectively.

The study found:

- The percentage of aorta sinus plaque to lumen area of 1% and 2% betaine groups were 41% and 33% smaller than that of the model group.

- Serum TNF-alpha level of three betaine groups were lower than that of the model group, but there was no significant difference in the methylation status of TNF-alpha promotor among all five groups.

They concluded that betaine could inhibit the development of atherosclerosis via anti-inflammation.

Fan et al (2008). "Anti-atherosclerotic effect of betaine in apolipoprotein E-deficient mice." Zhonghua Yu Fang Yi Xue Za Zhi 42(10): 742-7.