Nonalcoholic Steatohepatitis is associated with a state of betaine-insufficiency

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two-stage case-control study, which included patients with biopsy-proven NAFLD in order to explore circulating levels of betaine and its association with the histological spectrum. We also explored the association between a missense p.Ser646Pro variant in DMGDH (dimethylglycine dehydrogenase mitochondrial) and NAFLD severity (n =390).
RESULTS: In the discovery phase (n = 48), betaine levels were associated with the disease severity (p = 0.0030), including liver inflammation (Spearman R: - 0.51, p = 0.001), ballooning degeneration (R: - 0.50, p = 0.01), and fibrosis (R: - 0.54, p = 0.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis (NASH) in comparison with nonalcoholic fatty liver (NAFL). Further replication (n = 51) showed that betaine levels were associated with advanced NAFLD (p = 0.0085), and patients with NASH had a 1.26-fold decrease in betaine levels compared with those with NAFL. The rs1805074 was significantly associated with the disease severity (p = 0.011).
CONCLUSION: NAFLD severity is associated with a state of betaine-insufficiency.

Sookoian, S., et al., Nonalcoholic Steatohepatitis is associated with a state of betaine-insufficiency. Liver Int, 2016.

Serum betaine but not choline is inversely associated with breast cancer risk: a case-control study in China

PURPOSE: Choline and betaine are important for DNA methylation and synthesis, and may affect tumor carcinogenesis. To our knowledge, no previous study has examined the association between serum choline and betaine and breast cancer risk. This study aimed to examine whether serum choline and betaine were inversely associated with breast cancer risk among Chinese women. METHODS: This hospital-based case-control study consecutively recruited 510 breast cancer cases and 518 frequency-matched (age and residence) controls, and blood samples were available for 500 cases and 500 controls. Serum choline and betaine were assayed by high-performance liquid chromatography-tandem mass spectrometry. Multiple unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS: An inverse association with breast cancer risk was observed for serum betaine (fourth vs first quartile adjusted OR 0.68, 95 % CI 0.47-0.97) and for the ratio of serum betaine to choline (fourth vs first quartile adjusted OR 0.70, 95 % CI 0.48-1.00), but not for serum choline (fourth vs first quartile adjusted OR 0.80, 95 % CI 0.56-1.15). Serum betaine was inversely associated with breast cancer risk in subjects with below-median dietary folate intake (fourth vs first quartile adjusted OR 0.48, 95 % CI 0.30-0.77). CONCLUSIONS: This study suggested that serum betaine but not choline was inversely associated with breast cancer risk. This result needed to be further confirmed by the prospective studies.

Du, Y.F., et al., Serum betaine but not choline is inversely associated with breast cancer risk: a case-control study in China. Eur J Nutr, 2016.

Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model

Vascular dementia (VaD) is the second reason for the cognitive decline in aged people, but the effective therapy is still missing. The chronic cerebral hypoperfusion (CCH) had been widely found in VaD patients and is thought to be the key reason for cognitive impairment. Betaine is a natural product that had been implicated in many biological processes and had been used for the therapy of some neurodegenerative disease, such as Alzheimer's disease. In this study, we reported that betaine treatment could rescue the memory deficits induced by two-vessel occlusion (2-VO), a widely used CCH rat model. Betaine also restored the expression of PSD93, PSD95 and MAP2 to preserve the synaptic functions. Furthermore, betaine could reduce the oxidative stress by suppressing the MDA and ROS and enhancing the SOD and GSH. Overall, betaine treatment is able to rescue the memory deficits in CCH rats, which provide an experimental basis for the therapy of VaD.

Chunjie, N., et al., Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model. Neurosci Lett, 2015.

Betaine prevented fructose-induced NAFLD by regulating LXRalpha/PPARalpha pathway and alleviating ER stress in rats

Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up-regulated hepatic expression of liver X receptor-alpha (LXRalpha) and peroxisome proliferator-activated receptor-alpha (PPARalpha), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1alpha, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase alpha, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRalpha and PPARalpha expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD.

Ge, C.X., et al., Betaine prevented fructose-induced NAFLD by regulating LXRalpha/PPARalpha pathway and alleviating ER stress in rats. Eur J Pharmacol, 2015.

Betaine reduces plasma triglycerides and increases butyrylcholinesterase activity

The physiological function of butyrylcholinesterase (EC 3.1.1.8., BChE) is not clearly understood, but a role was suggested in the fat utilization process, resulting in positive correlation between plasma triglyceride (TG) levels and BChE activity. Consequently we tested the hypothesis that regular intake of betaine, a natural compound intervening in the liver TG metabolism could influence the BChE activity. The BChE activity was estimated spectrophotometrically in plasma of rats fed with betaine enriched standard (B) or high-fat diet (HFB). The results confirmed decreased TG plasma levels after betaine treatment independently on the type of diet (0.15+/-0.03 (B) vs. 0.27+/-0.08 (control) mmol/l; p=0.003 and 0.13+/-0.03 (HFB) vs. 0.27+/-0.08 (control) mmol/l; p=0.005). The BChE activity increased significantly with betaine administration, however the change was more distinct in the HFB group. In conclusion, betaine intake led to elevated BChE activity in plasma and this effect was potentiated by the HF diet. Since betaine is in general used as a supplement in the treatment of liver diseases accompanied by TG overload, its impact on the BChE activity in the role of the liver function marker should be taken into account.

Siskova, K., et al., Betaine increases the butyrylcholinesterase activity in rat plasma. Physiol Res, 2015.

Inhibition of insulin fibrillation by osmolytes

We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies.

Choudhary, S., N. Kishore, and R.V. Hosur, Inhibition of insulin fibrillation by osmolytes: Mechanistic Insights. Sci Rep, 2015. 5: p. 17599.

Maternal betaine supplementation during gestation enhances gene expression in skeletal muscle of newborn piglets

Betaine has been widely used in animal and human nutrition to promote muscle growth and performance, yet it remains unknown whether maternal betaine supplementation during gestation affects the metabolic characteristics of neonatal skeletal muscles. In the present study, feeding sows with betaine-supplemented diets throughout gestation significantly up-regulated the expression of mtDNA-encoded OXPHOS genes including COX1, COX2 and ND5, in the muscle of newborn piglets, which was associated with enhanced mitochondrial COX enzyme activity. Concurrently, maternal betaine supplementation increased plasma betaine concentration and muscle expression of methyl transfer enzymes, BHMT and GNMT in offspring piglets. Nevertheless, Dnmt3a was down-regulated at the level of both mRNA and protein, which was associated with hypomethylated mtDNA D-loop region. These results suggest that maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in skeletal muscle of newborn piglets.

Jia, Y., et al., Maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in skeletal muscle of newborn piglets. J Agric Food Chem, 2015.