Betaine in Inflammation: Mechanistic Aspects and Applications

Abstract

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.

Keywords: betaine; endoplasmic reticulum; inflammation; obesity; oxidative stress.

Figure 1

(A) Molecular structure of betaine. (B) Metabolism of betaine and related sulfur amino acids (SAAs). Betaine is a substrate of choline and can be converted to DMG via demethylation to ultimately become glycine. Most of these reactions occur in the mitochondria. The demethylation reaction converts homocysteine to methionine and can be replaced by 5-methyl-THF, which can catalyze methylation to form THF. Then, methionine is successively converted to SAM and finally to homocysteine to form the methionine cycle. Homocysteine can also go through the transsulfuration pathway to form cystathionine, cysteine, taurine, or glutathione. The enzymes mentioned in this review are shown and marked in the cycle with individual numbers. 1. Betaine-homocysteine methyltransferase (BHMT); 2. Methionine synthase (MS); 3. Methionine adenosyltransferase (MAT); 4. SAM-dependent methyltransferases; 5. S-adenosylhomocysteine hydrolase; 6. Cystathionine β-synthase (CBS); 7. Cysteine dioxygenase (CDO); 8. γ-glutamylcysteine synthetase (GCS). THF, tetrahydrofolate; SAM, S-adenosyl-L-methionine; SAH S-adenosyl-L-homocysteine; DMG, N,N-dimethylglycine.

Figure 2

Primary anti-inflammatory mechanisms of betaine. First, betaine can alter various sulfur amino acid (SAA) concentrations via protecting SAA metabolism from oxidative stress. Second, betaine can inhibit IKK, MAPKs, HDAC3, and Toll-like receptor-4 (TLR-4) activities to downregulate the nuclear factor- κB (NF-κB) pathway and pro-inflammatory genes transcription. Third, betaine can reduce the expression levels of NLRP3 inflammation components (pro-caspase-1, ASC, and NLRP3) and inhibit the FOXO-1-induced NLRP3 inflammasome via enhancing the IRS/Akt pathway. Fourth, betaine significantly increases activated AMPK, restores adipokines that can activate AMPK, and activates other lipid metabolism-related factors to regulate lipid metabolism. Fifth, on the one hand, betaine increases phosphorylated IRS, which phosphorylates Akt at threonine 308, to improve glucose metabolism. On the other hand, betaine can influence other glucose metabolism-related factors to improve glucose metabolism. Sixth, betaine can inhibit caspase-3 to reduce apoptosis and repair endoplasmic reticulum (ER) stress. Akt, protein kinase B; AMPK, AMP-activated protein kinase; FOXO-1, forkhead box O1; TXNIP, thioredoxin-interacting protein; ROS, reactive oxygen species; IKK, nuclear factor-inducing kinase/IκB kinase; MAPKs, mitogen-activated protein kinases; HDAC3, histone deacetylases 3. SAM, S-adenosyl-L-methionine; SAH S-adenosyl-L-homocysteine; GSH, glutathione; Met, methionine; Cys, cysteine.