Role of transmethylation reactions in alcoholic liver disease.
Alcoholic liver disease is a major health care problem worldwide. Findings from many laboratories, including ours, have demonstrated that ethanol feeding impairs several of the many steps involved in methionine metabolism. Ethanol consumption predominantly results in a decrease in the hepatocyte level of S-adenosylmethionine and the increases in two toxic metabolites, homocysteine and S-adenosylhomocysteine. These changes, in turn, result in serious functional consequences which include decreases in essential methylation reactions via inhibition of various methyltransferases. Of particular interest to our laboratory is the inhibition of three important enzymes, phosphatidylethanolamine methyltransferase, isoprenylcysteine carboxyl methyltransferase and protein L-isoaspartate methyltransferase. Decreased activity of these enzymes results in increased fat deposition, increased apoptosis and increased accumulation of damaged proteins-all of which are hallmark features of alcoholic liver injury. Of all the therapeutic modalities available, betaine has been shown to be the safest, least expensive and most effective in attenuating ethanol-induced liver injury. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, and reverses steatosis, apoptosis and damaged proteins accumulation. In conclusion, betaine appears to be a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.
Kharbanda
Kusum K
KK
Department of Veterans Affairs Medical Center, Research Service 151, 4101 Woolworth Avenue, Omaha, Nebraska 68105, USA. kkharbanda@unmc.edu
D001622:Betaine / Q000627:therapeutic use; D006801:Humans; D008082:Lipotropic Agents / Q000627:therapeutic use; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000378:metabolism
D008082:Lipotropic Agents; D001622:Betaine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D008780:Methyltransferases