Alcoholic Liver Disease and Methionine Metabolism

Abstract

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.

Role of plasma amino acids and gaba in alcoholic and non-alcoholic fatty liver disease-a pilot study

“…Alcoholic liver disease patients showed significantly increased plasma levels of methionine compared to other two groups in this study (Table 1) is also in agreement with other studies (14,18) and probably result from impaired hepatic metabolism and portal systemic shunting of blood (8). Ethanol feeding impairs several of the multiple steps in methionine metabolism that leads to progressive liver injury (25). Moreover, GABA is significantly correlated with methionine level (Table 2).…”

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

“…Previous studies have shown that Ach can inhibit AKT activity, while Ach or ethanol results in proapoptotic posttranslational modifications to the transcrip- tion factor FoxO3 (30). The combination of ethanol, or its major metabolite acetaldehyde, plus HCV further dysregulates FoxO3 (55) and alters methylation reactions in cells (17), which usually are protective from apoptosis in the liver (25). Here, we additionally found that the combination increased expression of miR-34a, a known apoptosis inducer that targets silent information regulator 1 (SIRT1) expression and causes p53 acetylation (44,52,58,60).…”

Betaine chemistry, roles, and potential use in liver disease

“…Similar to its action in NAFLD, betaine has been reported to be protective of liver injury in animal models of ALD [81][82][83]. The enzyme methionine synthase, a vital enzyme for remethylation of homocysteine via the folate cycle, is inhibited by ethanol consumption [84,85] and this may account for an increase in homocysteine in plasma. Under these conditions, dietary supplements of betaine likely provide an alternative pathway for remethylation of homocysteine via BHMT in the methionine cycle (Fig.…”