Alcoholic liver disease is a major health care problem worldwide. Findings have demonstrated that
ethanol feeding impairs several of the multiple steps in
methionine metabolism that leads to progressive liver injury.
Ethanol consumption has been reported to predominantly inhibit the activity of a vital cellular
enzyme,
methionine synthase, involved in remethylating
homocysteine. By way of compensation in some species,
ethanol can also increase the activity of the
enzyme,
betaine homocysteine methyltransferase. This
enzyme catalyzes an alternate pathway in
methionine metabolism and utilizes hepatic
betaine to remethylate
homocysteine to form
methionine and maintain levels of
S-adenosylmethionine, the key methylating agent. Under extended periods of
ethanol feeding, however, this alternate pathway cannot be maintained. This results in a decrease in the hepatocyte level of
S-adenosylmethionine and increases in two toxic metabolites,
S-adenosylhomocysteine and
homocysteine. These changes in the various metabolites of
methionine metabolism, in turn, result in serious functional consequences. These include decreases in essential methylation reactions by inhibiting various
methyltransferases critical to normal functioning of the liver and upregulation of the activation of endoplasmic reticulum-dependent apoptosis and
lipid synthetic pathways. The ultimate outcome of these consequences is increased fat deposition, increased apoptosis, accumulation of damaged
proteins, and alterations in various signaling pathways, all of which can ultimately result in progressive liver damage. Of all the therapeutic modalities that are presently being 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.
Betaine, by virtue of aiding in the remethylation of
homocysteine, removes both toxic metabolites (
homocysteine and
S-adenosylhomocysteine), restores
S-adenosylmethionine level, reverses steatosis, prevents apoptosis and reduces both damaged
protein accumulation and oxidative stress. Thus,
betaine is a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.