High homocysteine induces betaine depletion

Betaine is the substrate of the liver- and kidney- specific betaine-homocysteine methyltransferase (BHMT), an alternate pathway for homocysteine remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any homocysteine interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of CBS deficiency. S-adenosyl-methionine, S-adenosyl-homocysteine, methionine, betaine, and dimethylglycine were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease of the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

Imbard, A., et al., High homocysteine induces betaine depletion. Biosci Rep, 2015.

Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet

To assess the effects of betaine on hepatic lipid accumulation and investigate the underlying mechanism, thirty-two male Sprague-Dawley rats weighing 100 (sd 2.50) g were divided into four groups, and started on one of four treatments: basal diet, basal diet with betaine administration, high-fat diet and high-fat diet with betaine administration. The results showed that no significant difference of body weight was found among experimental groups. Compared with high-fat diet-fed rats, a betaine supplementation decreased (P< 0.05) hepatic TAG accumulation induced by high-fat diet, which was also supported by hepatic histology results. Additionally, hepatic betaine-homocysteine methyltransferase activity as well as its mRNA abundance and lecithin level were found increased (P< 0.05) by betaine supplementation in both basal diet-fed rats and high-fat diet-fed rats. Betaine administration in high-fat diet-fed rats exhibited a higher (P< 0.05) activity of hepatic carnitine palmitoyltransferase 1 (CPT1) compared with high-fat diet-fed rats. High-fat diet inhibited (P< 0.05) the gene expression of hepatic PPARalpha and CPT1. However, betaine administration in high-fat diet-fed rats elevated (P< 0.05) the gene expression of PPARalpha and CPT1. Moreover, concentration, gene and protein expressions of hepatic fibroblast growth factor 21 (FGF21) were increased (P< 0.05) in response to betaine administration in high-fat diet group; meanwhile the gene expression of hepatic AMP-activated protein kinase was increased (P< 0.05) as well. The results suggest that betaine administration enhanced hepatic lipid export and fatty acid oxidation in high-fat diet-fed rats, thus effectively alleviating fat accumulation in the liver.

Xu, L., et al., Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet. Br J Nutr, 2015: p. 1-9

Betaine exhibits tumoricidal effects and acts as a biological response modifier in cancer treatment by inducing apoptosis and cell cycle arrest

OBJECTIVES: To investigate the effects of betaine on HeLa cell growth and apoptosis and molecular mechanisms.
MATERIALS AND METHODS: Concentrations of 0.1, 1.0, 5.0, 20.0, 100.0 mg/ml of betaine were used to evaluate the anticancer efficacy for HeLa cells respectively, and MCF-10A was also detected as a normal diploid cell control.
RESULTS: We found that proliferation of HeLa cells was inhibited significantly upon exposure to increasing betaine levels with the MTT test. The percentage of S phase cells in the low dose groups (< 5mg/ml) were distinctly higher than in high dose groups, and the rates of Sub-G1 phase were the opposite; A high concentration of betaine (>5.0mg/ml) significantly promoted the apoptosis of HeLa cells. SOD activities of the low dose groups were slightly higher than the control group and there were obvious synchronicity and correlation among the expression of promoting apoptosis genes Bax, P53, Caspase 3 and apoptosis suppression gene Bcl-2. In response to an apoptosis-inducing stimulus, p53 and cyclin D1 could be activated with blockage of the cell cycle at G1/S or S/G2 checkpoints.
CONCLUSIONS: Our data showed that betaine could promote HeLa cells proliferation in vitro at low concentrations.In contrast, high concentrations could significantly inhibit cell growth and migration, and induce apoptosis of HeLa cells through caspase 3 signaling and further promoted necrosis. This might imply that betaine exhibits tumoricidal effects and acts as a biological response modifier in cancer treatment by inducing apoptosis and cell cycle arrest in a dose and time-dependent manner.

Guo, Y., et al., Betaine Effects on Morphology, Proliferation, and p53-induced Apoptosis of HeLa Cervical Carcinoma Cells in Vitro. Asian Pac J Cancer Prev, 2015. 16(8): p. 3195-201

Betaine attenuates alcohol-induced leaky gut through BHMT-mediated catalysis

Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complex; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD.

Thomes, P.G., et al., Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity. Biochem Pharmacol, 2015.

Betaine inhibits vascularization via suppression of Akt in the retinas of streptozotocin-induced hyperglycemic rats

Diabetic retinopathy is a severe microvascular complication amongst patients with diabetes, and is the primary cause of visual loss through neovascularization. Betaine is one of the components of Fructus Lycii. In the present study, the effects of betaine on the expression levels of vascular endothelial growth factor (VEGF) and hypoxiainducible factor (HIF)1alpha in association with the Akt pathway were investigated in the retinas of streptozotocin (STZ)induced diabetic rats using western blot and immunohistochemical analyses. The results of the present study revealed that the expression levels of VEGF, HIF1alpha, and Akt were increased in the retinas of the STZinduced diabetic rats. Betaine treatment attenuated this increase in VEGF and HIF1alpha expression via suppression of diabetesinduced Akt activation in the retinas of the diabetic rats. The results suggested that betaine may potentially be used to delay the onset of complications associated with diabetic retinopathy via inhibition of retinal neovascularization in patients with diabetes.

Kim, Y.G., et al., Betaine inhibits vascularization via suppression of Akt in the retinas of streptozotocin-induced hyperglycemic rats. Mol Med Rep, 2015