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Targeting Liver Pathways: Betaine's Molecular Mechanisms in Liver Diseases

Milena Veskovic

Institute Of Pathophysiology, Faculty Of Medicine University Of Belgrade, Belgrade, Serbia

Recieved on: 2024-01-15, Accepted on: 2024-02-06, Published on: 2024-02-12




Liver diseases, encompassing a spectrum from fatty liver to cirrhosis, represent a global health problem. Betaine, a methyl donor derived from choline, has garnered attention for its potential in ameliorating liver pathology.

Betaine's hepatoprotective effects are prominently observed through the regulation of lipid metabolism. Studies have shown that betaine reduces hepatic triglyceride accumulation by modulating key enzymes involved in lipogenesis and lipid oxidation. It promotes the expression of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor crucial for fatty acid oxidation, thus enhancing lipid catabolism and attenuating hepatic steatosis [1].

Liver diseases are usually followed by increased oxidative stress, contributing to inflammation and further tissue damage. Betaine acts as a potent antioxidant by promoting the synthesis of glutathione, a critical cellular antioxidant. This molecular mechanism strengthens the liver's defense against reactive oxygen species (ROS), mitigating oxidative damage and inflammation. Betaine's impact on oxidative stress in liver disease involves intricate molecular mechanisms. One key feature is betaine's role as a methyl donor in the methionine-homocysteine cycle. By facilitating methylation reactions, betaine contributes to the maintenance of cellular function, influencing gene expression and protein function. Additionally, betaine acts as an antioxidant by directly scavenging ROS and enhancing the activities of endogenous antioxidant enzymes, such as superoxide dismutase and catalase. Furthermore, betaine has been shown to modulate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor pivotal in regulating the cellular antioxidant response. This multifaceted approach enables betaine to mitigate oxidative stress, protecting liver cells from damage and inflammation.

In the progression of liver diseases inflammatory responses play a pivotal role. Betaine was shown to exert anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB) activation, a key regulator of pro-inflammatory cytokines. Additionally, betaine modulates immune cell function, suppressing the release of inflammatory mediators such as tumor necrosis factor and interleukin-6 and fostering an anti-inflammatory microenvironment within the liver promoting the expression of anti-inflammatory interleukin-10 [2].

Recently, betaine's impact on autophagy in liver disease became the interesting potentially protective mechanism. Research indicates that betaine may activate the AMP-activated protein kinase (AMPK) pathway, a key regulator of cellular energy homeostasis. AMPK activation, in turn, can stimulate autophagy by inhibiting the mammalian target of rapamycin (mTOR). Additionally, betaine has been shown to enhance the expression and activity of Beclin-1, a crucial autophagy-related protein. By modulating these molecular pathways, betaine may facilitate the clearance of damaged organelles and proteins, reducing cellular stress and inflammation in the liver. In addition, numerous research suggests that betaine may impact apoptotic pathways by regulating the B-cell lymphoma 2 (Bcl-2) family of proteins. This family controls the balance between pro-apoptotic and anti-apoptotic signals within cells. Betaine has demonstrated the ability to modulate Bcl-2 family members, influencing mitochondrial integrity and apoptotic cascades. Furthermore, betaine's role in mitigating oxidative stress, often implicated in liver diseases, can indirectly impact apoptotic pathways [2,3].

In conclusion, betaine emerges as a multifaceted therapeutic agent targeting diverse molecular pathways critical for liver health. From regulating lipid metabolism and combating oxidative stress to modulating inflammation and influencing epigenetic processes, betaine showcases a comprehensive molecular spectrum. As research advances, a deeper understanding of these precise mechanisms will undoubtedly pave the way for the development of targeted and effective interventions in liver diseases. The exploration of betaine's molecular intricacies opens new avenues for therapeutic strategies aimed at mitigating the global burden of liver pathologies.


  1. Rehman A, Mehta KJ (2022) Betaine in ameliorating alcohol-induced hepatic steatosis. Eur J Nutr 61(3): 1167-1176.
  2. Veskovic M, Mladenovic D, Milenkovic M, Tosic J, Borozan S, et al. (2019) Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. Eur J Pharmacol 848: 39-48.
  3. Graf D, Kurz AK, Reinehr R, Fischer R, Kircheis G, (2002) Prevention of bile acid-induced apoptosis by betaine in rat liver. Hepatology 36(4 Pt 1): 829-839.