Alcoholic liver disease and methionine metabolism

Alcoholic liver disease is a major health care problem worldwide. Results have shown that alcohol feeding impairs several of the multiple steps in methionine metabolism that lead to progressive liver injury.

Ethanol consumption has been reported to predominantly inhibit the activity of a vital cellular enzyme, methionine synthase, which is involved in the remethylation of homocysteine. As compensation, alcohol consumption in some species may also increase the activity of the enzyme betaine homocysteine methyltransferase. This enzyme catalyzes an alternative pathway in methionine metabolism and uses hepatic betaine to remethylate homocysteine to form methionine and maintain levels of S-adenosylmethionine, the major methylating agent.

However, with prolonged alcohol intake, this alternative metabolic pathway cannot be maintained. This leads to a decrease in S-adenosylmethionine levels in hepatocytes and an increase in two toxic metabolites, S-adenosylhomocysteine and homocysteine. These changes in the various metabolites of methionine metabolism in turn lead to serious functional consequences.

These include a decrease in essential methylation reactions through inhibition of various methyltransferases critical for normal liver function and upregulation of activation of endoplasmic reticulum-dependent apoptosis and lipid synthesis pathways. The ultimate result of these consequences is increased lipid deposition, increased apoptosis, accumulation of damaged proteins, and alterations in various signaling pathways, all of which may ultimately lead to progressive liver injury.

Of all the therapeutic modalities currently used to attenuate ethanol-induced liver injury, betaine has been shown to be the most effective in a variety of experimental models of liver disease. By supporting the remethylation of homocysteine, betaine removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine levels, reverses steatosis, prevents apoptosis, and reduces both the accumulation of damaged proteins and oxidative stress.

Thus, betaine is a promising therapeutic agent for relieving methylation and other defects associated with alcohol abuse.

Semin Liver Dis.: Alcoholic liver disease and methionine metabolism

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