Alcoholic Liver Disease and Methionine Metabolism

This review states that, "Of all the therapeutic modalities that are presently being used to attenuate ethanol-induced liver injury, betaine has been shown to be the most effective in a variety of experimental models of liver disease. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, reverses steatosis, prevents apoptosis and reduces both damaged protein accumulation and oxidative stress. Thus, betaine is a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse."

Kharbanda, K. K. (2009). Alcoholic liver disease and methionine metabolism. Semin Liver Dis, 29(2), 155-165.

Betaine prevents Mallory-Denk body formation

Drug-primed mice were fed betaine, together with DDC, which was refed for 7 days. Betaine:

- reduced Mallory-Denk body (MDB) formation (markers for liver disease)
- decreased the liver/body weight ratio
- decreased the number of FAT10 positive liver cells
- prevented the decreased expression of BHMT, AHCY, MAT1a and GNMT and the increased expression of MTHFR, caused by DDC refeeding
- prevented the rise in S-Adenosylhomocysteine (SAH) levels caused by DDC refeeding

Oliva et al (2009). "Betaine prevents Mallory-Denk body formation in drug-primed mice by epigenetic mechanisms." Exp Mol Pathol 86(2): 77-86.

Reducing IR and NAFLD

This is an abstract from the 2008 AASLD meeting. Rats were fed one of 3 diets for 8 months:

- standard chow (SF) (9% cal for fat)
- high fat (HF) (20% cal from fat)
- HF plus betaine (HF+B) (1.5% betaine in drinking water)

In this high fat diet-induced model of insulin resistance and NAFLD, oral betaine:

- reduced fasting insulin and glucose
- reversed hepatic steatosis
- increased activation of the insulin signaling pathway
- reversed hepatic insulin resistance, as demonstrated by reduced gluconeogenesis and increased glycogen content

Kathirvel et al (2008). "Betaine reduces insulin resistance and hepatic steatosis, and augments hepatic signaling, in an animal model of NAFLD." Hepatology 48(S1): 408A-505A.

Betaine and homocysteine

In a randomized crossover study, 8 healthy males (22–36 y) consumed either a betaine-rich diet (800 mg/day) or a betaine supplement (0.5 g twice daily) for 14 days. Fasting blood samples were collected on day −5, −1 (pre-treatment) 0, 2, 6, 9, 13 (treatment), 14 and 18 (post-treatment). Post-methionine load blood samples were collected on day −5, 0, 6 and 13, while 24 h urine samples were collected on day −5, 0, 6, 13 and 14. Plasma betaine, dimethylglycine, homocysteine and urine betaine, dimethylglycine and creatinine concentrations were measured.

Plasma betaine concentrations significantly increased for both treatments compared to pre-treatment values (P < 0.001). Fasting homocysteine levels were minimally affected. Both treatments reduced post-methionine load homocysteine and this effect tended to be greater following a betaine-rich diet (P = 0.108). Small increases in urinary betaine excretion were observed following both treatments (≈1.5% of supplement; ≈1.3% of dietary betaine). Most was attributable to increased excretion of betaine as dimethylglycine.

Therefore, supplemental or dietary betaine similarly increase circulating betaine concentrations and attenuate the post-methionine load rise in homocysteine concentrations.

Atkinson et al (2009). "Dietary and supplementary betaine: Effects on betaine and homocysteine concentrations in males." Nutr Metab Cardiovasc Dis. Apr 3 Epub.

One carbon metabolism and birth defects

The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B6, vitamin B12, riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD).

They analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants.

TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

Robitaille et al (2009). "Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: Data from the National Birth Defects Prevention Study, 1997-2003." Birth Defects Research Part A: Clinical and Molecular Teratology. March 1 Epub.

Effect of casein diet on hepatic BHMT and betaine

Study 1 - male Wistar rats were fed diets differing in casein level from 5 to 50% for 14 d. Plasma total homocysteine concentration was positively correlated with dietary casein level in the range of 5 to 10% but inversely correlated with dietary casein level in the range of 10 to 50%. Hepatic cystathionine β-synthase (CBS) and betaine-homocysteine S-methyltransferase (BHMT) activities and renal CBS activity increased in response to dietary casein level in the range of 10 to 50%, whereas hepatic serine and betaine concentrations decreased with increasing dietary casein levels.

Study 2 - rats were fed a 10% casein diet or 10% casein+17.2% amino acid mixture diet for 14 d. Plasma homocysteine concentration was significantly lower in rats fed the amino acid mixture-added diet than in rats fed the 10% casein diet, indicating that the hypohomocysteinemic effect of high casein diets was elicited by amino acids, not by casein contaminants.

Study 3 - the degree of increase in plasma homocysteine concentration caused by dietary supplementation with 0.75% L-methionine was significantly lower in rats fed the 40% casein diet than in rats fed the 10% casein diet.

These results indicate that high casein diets do not increase but rather decrease plasma homocysteine concentration and cause resistance to hyperhomocysteinemic treatment, and suggest that such effects of high casein diets are mediated at least by increased activities of CBS and BHMT.

Ohuchi et al (2009). "High casein diet decreases plasma homocysteine concentration in rats." J Nutr Sci Vitaminol (Tokyo) 55(1): 22-30.

Protection against myocardial infarction

This study investigated the protective effect of betaine on changes in the levels of membrane-bound ATPase activities, lipid peroxidation, sulfhydryl activities, and mineral status in isoprenaline-induced myocardial infarction in Wistar rats, an animal model of myocardial infarction in man. Oral administration of betaine (250 mg/kg body weight/day for a period of 30 days) significantly (p < 0.05) improved the following isoprenaline-induced abnormalities:

- maintained levels of sodium, potassium, and calcium in plasma and heart tissue
- protected membrane-bound ATPase in the heart tissue
- preserved myocardial sulfhydryl activities
- counteracted lipid peroxidation

Ganesan et al (2009). "Protective effect of betaine on changes in the levels of membrane-bound ATPase activity and mineral status in experimentally induced myocardial infarction in Wistar rats." Biological Trace Element Research. April 8 Epub

Osmolyte protection against urea denaturation of chymotrypsin

The destabilizing effect of urea on proteins can be counteracted by methylamines (osmolytes), such as trimethylamine N-oxide (TMAO), betaine, and sarcosine. This study compared the counteracting effects of these methylamines on urea-induced denaturation of α-chymotrypsin (CT). They measured the hydrodynamic diameter (dH) and the thermodynamic properties (Tm, ΔH, ΔGU, and ΔCp) with dynamic light scattering (DLS) and differential scanning calorimeter (DSC), respectively. The osmolytes strongly counteracted the urea actions on α-chymotrypsin, with TMAO having the strongest effect.

Venkatesu et al (2009). "Osmolyte Counteracts Urea-Induced Denaturation of alpha-Chymotrypsin." The Journal of Physical Chemistry B 113(15): 5327-5338.