Hepatic transmethylation reactions in micropigs with alcoholic liver disease.
Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of S-adenosylmethionine (SAM) and glutathione (GSH). The concept that abnormal methionine metabolism is involved in the pathogenesis of alcoholic liver disease was strengthened by our previous findings in a micropig model where combining dietary folate deficiency with chronic ethanol feeding produced maximal changes in these metabolites together with early onset of microscopic steatohepatitis and an eightfold increase in plasma aspartate aminotransferase. The goal of the present study was to determine potential mechanisms for abnormal levels of these methionine metabolites by analyzing the transcripts and activities of transmethylation enzymes in the livers of the same micropigs. Ethanol feeding or folate deficiency, separately or in combination, decreased transcript levels of methylenetetrahydrofolate reductase (MTHFR), methionine adenosyltransferase (MAT1A), glycine-N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (SAHH). Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT. Each diet, separately or in combination, decreased the activities of MTHFR and SAHH. In conclusion, the observed abnormal levels of methionine metabolites in this animal model of accelerated alcoholic liver injury can be ascribed to specific effects of ethanol with or without folate deficiency on the expressions and activities of hepatic enzymes that regulate transmethylation reactions. These novel effects on transmethylation reactions may be implicated in the pathogenesis of alcoholic liver disease.
Villanueva
Jesus A
JA
Department of Internal Medicine, University of California Davis, Davis, CA 95616, USA.
Halsted
Charles H
CH
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics / Q000378:metabolism; D043383:Adenosylhomocysteinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D050938:Glycine N-Methyltransferase; D008099:Liver / Q000201:enzymology* / Q000503:physiopathology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000503:physiopathology*; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D013556:Swine, Miniature
D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D050938:Glycine N-Methyltransferase; D008716:Methionine Adenosyltransferase; D043383:Adenosylhomocysteinase