Alterations in methionine metabolic pathway in the pathogenesis of alcohol-related liver disease

Alcohol-related liver disease is a major worldwide health care problem. Findings in multiple laboratories, including ours, have demonstrated that ethanol consumption impairs several of the multiple steps in hepatic methionine metabolism, leading to progressive liver injury. Ethanol consumption predominantly inhibits the activity of the vital enzyme, methionine synthase, which catalyzes homocysteine remethylation to form methionine. By way of compensation, chronic ethanol consumption increases the activity of betaine homocysteine methyltransferase. This enzyme catalyzes an alternate pathway in methionine metabolism by utilizing intracellular betaine to remethylate homocysteine to form methionine, thereby maintaining adequate levels of S-adenosylmethionine, the key cellular methylating agent. However, after extended periods of ethanol feeding, alternate pathway for remethylation cannot be maintained, likely due to depletion in hepatic betaine levels. This condition, in turn, results in a decrease in hepatocyte S-adenosylmethionine, while increasing the levels of two toxic metabolites, S-adenosylhomocysteine and homocysteine. These changes cause serious functional consequences, which include lower activities of essential methylation reactions critical to normal liver function and activation of endoplasmic reticulum-dependent stress response. The ultimate outcome of these consequences is enhanced fat deposition, increased apoptosis, accumulation of damaged proteins and alterations in various signaling pathways, all of which, if sustained, cause progressive liver damage. Of all the therapeutic modalities currently used to attenuate ethanol-induced liver injury, betaine has been shown to be one of the most effective in a variety of experimental models of liver disease. Betaine, as a methyl group donor, remethylates homocysteine, thereby removing both toxic metabolites (homocysteine and S-adenosylhomocysteine) and restoring S-adenosylmethionine to reverse/prevent many hallmark features of alcohol-induced liver damage. Thus, betaine is a promising therapeutic agent that relieves methylation and other defects associated with alcohol use disorders.