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Deletion of glycine N‐methyltransferase (GNMT), the main gene involved in liver S‐adenosylmethionine (SAM) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis in mice. To demonstrate that the excess of hepatic SAM is the main agent contributing to liver disease in GNMT knockout (KO) mice, we treated 1.5‐month‐old GNMT‐KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N‐methyltransferase. NAM administration markedly reduced hepatic SAM content, prevented DNA hypermethylation, and normalized the expression of critical genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More importantly, NAM treatment prevented the development of fatty liver and fibrosis in GNMT‐KO mice. Because GNMT expression is down‐regulated in patients with cirrhosis, and because …