Betaine in Inflammation: Mechanistic Aspects and Applications.
Zhao Guangfu,He Fang,Wu Chenlu,Li Pan,Li Nengzhang,Deng Jinping,Zhu Guoqiang,Ren Wenkai,Peng Yuanyi
Frontiers in immunology
Betaine is known as trimethylglycine and is widely distributed in animals, plants, and microorganisms. Betaine is known to function physiologically as an important osmoprotectant and methyl group donor. Accumulating evidence has shown that betaine has anti-inflammatory functions in numerous diseases. Mechanistically, betaine ameliorates sulfur amino acid metabolism against oxidative stress, inhibits nuclear factor-κB activity and NLRP3 inflammasome activation, regulates energy metabolism, and mitigates endoplasmic reticulum stress and apoptosis. Consequently, betaine has beneficial actions in several human diseases, such as obesity, diabetes, cancer, and Alzheimer's disease.
10.3389/fimmu.2018.01070
Evaluation of dietary betaine in lactating Holstein cows subjected to heat stress.
Hall L W,Dunshea F R,Allen J D,Rungruang S,Collier J L,Long N M,Collier R J
Journal of dairy science
Betaine (BET), a natural, organic osmolyte, improves cellular efficiency by acting as a chaperone, refolding denatured proteins. To test if dietary BET reduced the effect of heat stress (HS) in lactating dairy cows, multiparous, lactating Holstein cows (n=24) were blocked by days in milk (101.4±8.6 d) and randomly assigned to 1 of 3 daily intakes of dietary BET: the control (CON) group received no BET, mid intake (MID) received 57mg of BET/kg of body weight, and high dose (HI) received 114mg of BET/kg of body weight. Cows were fed twice daily and BET was top-dressed at each feeding. Cows were milked 2 times/d and milk samples were taken daily for analysis. Milk components, yield, feed intake, and water intake records were taken daily. Rectal temperature and respiration rate were taken 3 times/d at 0600, 1400, and 1800h. Cows were housed in environmentally controlled rooms and were allowed acclimation for 7d at thermoneutral (TN) conditions with a mean temperature-humidity index of 56.6. Cows were then exposed to 7d of TN followed by 7d of HS represented by a temperature-humidity index of 71.5 for 14d. This was followed by a recovery period of 3d at TN. Dietary BET increased milk yield during the TN period. No differences were found between BET and CON in total milk production or milk composition during HS. The increase in water intake during HS was not as great for cows fed BET compared with controls. The cows on CON diets had higher p.m. respiration rate than both MID and HI BET during HS, but lower rectal temperature compared with BET. No difference was found in serum glucose during TN, but cows given HI had elevated glucose levels during HS compared with CON. No differences were found in serum insulin levels between CON and BET but an intake by environment interaction was present with insulin increasing in HI-treated lactating dairy cows during HS. The heat shock response [heat shock protein (HSP) 27 and HSP70] was upregulated in bovine mammary epithelial cells in vitro. Blood leukocyte HSP27 was downregulated at the HI dose under TN conditions and HSP70 was upregulated at the HI dose and this effect was increased by HS. No effect was seen with the MID dose with HSP27 or HSP70. The lack of effect of BET at MID may be associated with uptake across the gut. We conclude that BET increased milk production under TN conditions and was associated with reduced feed and water intake and slightly increased body temperatures during HS of cows fed BET. The effect of BET on milk production was lost during HS with HI BET, whereas serum glucose levels increased during HS.
10.3168/jds.2015-10514
Betaine protects against heat exposure-induced oxidative stress and apoptosis in bovine mammary epithelial cells via regulation of ROS production.
Cell stress & chaperones
Heat stress is one of the wide varieties of factors which cause oxidative stress in vivo; elevated temperature can lead to oxidative stress of dairy cows that affects milk production. The aim of this study was to determine the capacity of the betaine to act as an antioxidant against oxidative stress induced by heat exposure and apoptosis in mammary epithelial cells (mammary alveolar cells, MAC-T). The MAC-T were divided into four treatment groups: control (37 °C), heat stress (HS, 42 °C), betaine (37 °C), and HS + betaine. MAC-T under heat stress (HS) showed increased ROS accumulation, malondialdehyde (MDA) content, superoxide dismutase (SOD) concentration, and catalase (CAT) activity. During heat stress, betaine decreased the mRNA expression level of HSP70 and HSP27 in MAC-T. Bax/Bcl-2 ratio and caspase-3, the markers of apoptosis, were also elevated in MAC-T under heat stress. The markers of oxidative stress Nrf-2/HO-1 genes were also elevated in MAC-T under heat stress. Pretreatment of betaine reversed the heat-induced depletion in total antioxidant status, ROS accumulation, and SOD and CAT contents in MAC-T. Bax/Bcl-2 ratio and Nrf-2/HO-1 expression of heat-exposed MAC-T were also reduced with betaine supplementation. In conclusion, betaine alleviated oxidative stress and apoptosis of MAC-T by inhibiting ROS accumulation.
10.1007/s12192-019-00982-4
Choline and betaine in health and disease.
Ueland Per Magne
Journal of inherited metabolic disease
Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine-homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B₂, B₆, and B₁₂) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.
10.1007/s10545-010-9088-4
The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMP-activated protein kinase α1 subunit.
Zhou Xihong,Chen Jingqing,Chen Jin,Wu Weiche,Wang Xinxia,Wang Yizhen
The Journal of nutritional biochemistry
The current study was conducted to determine whether betaine could improve fatty acid oxidation, mitochondrial function and N6-methyladenosine (m(6)A) mRNA methylation in adipose tissue in high-fat-induced mice and how AMP-activated protein kinase α1 subunit (AMPKα1) was involved. AMPKα1 knockout mice and wild-type mice were fed either a low-fat diet, high-fat diet or high-fat diet supplemented with betaine in the drinking water for 8weeks. Our results showed that mitochondrial genes (PGC1α) and β-oxidation-related genes (CPT1a) at protein level were increased in wild-type mice supplemented with betaine when compared with those in mice with high-fat diet. Betaine also decreased FTO expression and improved m(6)A methylation in adipose tissue of wild-type mice with high-fat diet. However, betaine failed to exert the abovementioned effects in AMPKα1 knockout mice. In adipocytes isolated from mice with high-fat diet, betaine treatment increased lipolysis and lipid oxidation. Moreover, betaine decreased FTO expression and increased m(6)A methylation. However, while AMPKα1 was knockdown, no remarkable changes in adipocytes were observed under betaine treatment. Our results indicated that betaine supplementation rectified mRNA hypomethylation and high FTO expression induced by high-fat diet, which may contribute to its beneficial effects on impaired adipose tissue function. Our results suggested that the AMPKα1 subunit is required for the beneficial effects of betaine on dysfunctional adipose tissue and m(6)A methylation. These results may provide the foundation for a mechanism that links m(6)A methylation status in RNA, AMPKα1 phosphorylation and dysfunctional adipose tissue induced by high-fat diet.
10.1016/j.jnutbio.2015.08.014
Effects of niacin and betaine on bovine mammary and uterine cells exposed to thermal shock in vitro.
Xiao Y,Rungruang S,Hall L W,Collier J L,Dunshea F R,Collier R J
Journal of dairy science
The objective of this study was to investigate the direct effects of feed supplements niacin and betaine on the heat shock responses of in vitro cultured cells derived from bovine mammary and uterine tissues. First, we determined the mRNA expression profiles of the niacin receptor (GPR109A) in bovine tissues (liver, skin, uterus, udder, and ovary) and in cells derived from bovine mammary epithelium (mammary alveolar cells, MAC-T; bovine mammary epithelial cells, BMEC) and endometrium (bovine endometrial cells, BEND). We found that GPR109A was distributed in all examined tissues and cells, and the highest expression was in cells from skin and udder. Second, we evaluated the effects of niacin treatment on the mRNA abundance of heat shock proteins 70 and 27 (HSP70 and HSP27) in MAC-T, BMEC, and BEND under thermoneutral conditions and heat stress, and whether these effects were associated with alterations in the mRNA expression of prostaglandin E synthesis-related genes, including cyclooxygenase 1 and 2 (COX-1 and COX-2) and microsomal prostaglandin E synthase 1 and 2 (mPGES-1 and mPGES-2). Quantitative PCR data indicated that niacin suppressed HSP70 mRNA expression in BMEC and both HSP70 and HSP27 in BEND under thermoneutral conditions. Only COX-2 expression was downregulated by niacin in BMEC; other prostaglandin E synthesis-related genes stayed unaltered in BMEC and BEND. The mRNA abundance of HSP70, COX-1, COX-2, and mPGES-1 were elevated in niacin-treated MAC-T. During heat stress, niacin increased mRNA levels of HSP70 and HSP27 in MAC-T and HSP27 in BEND, but decreased HSP70 in BMEC. Although mPGES-2 was stimulated by niacin in BEND, the mRNA expression of prostaglandin E synthesis-related genes were consistent with neither HSP70 nor HSP27 expression patterns in niacin-treated BMEC and MAC-T. These data suggest that the effects of niacin on heat shock protein expression and prostaglandin E synthesis were not well coupled in these cells. Finally, we tested the effects of betaine treatment on viability and apoptosis in BMEC. Compared with control cultures, viability was higher in betaine-treated cells at 8 h under thermoneutral conditions and at 16 h in heat stress, and apoptotic rates were lower at 8 h. Our data support a dual role for niacin in regulating heat shock protein expression in normal and heat-shocked cells derived from mammary and uterine tissues, and positive effects of betaine in regulating mammary cell viability during heat stress.
10.3168/jds.2016-11876