Role of S-adenosyl-L-methionine in liver health and injury.
S-adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte growth, death, and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of all forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and hepatocellular carcinoma. However, impaired SAMe metabolism, which occurs in patients with mutations of glycine N-methyltransferase (GNMT), can also lead to liver injury. This suggest that hepatic SAMe level needs to be maintained within a certain range, and deficiency or excess can both lead to abnormality. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also show it is effective in patients with cholestatic liver diseases. Recent data show that exogenous SAMe can regulate hepatocyte growth and death, independent of its role as a methyl donor. This raises the question of its mechanism of action when used pharmacologically. Indeed, many of its actions can be recapitulated by methylthioadenosine (MTA), a by-product of SAMe that is not a methyl donor. A better understanding of why liver injury occurs when SAMe homeostasis is perturbed and mechanisms of action of pharmacologic doses of SAMe are essential in defining which patients will benefit from its use.
Mato
José M
JM
CIC-Biogune, Center for Cooperative Research in Biosciences, CIBER-HEPAD, Parque Tecnológico de Bizkaia, Derio, Bizkaia.
Lu
Shelly C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008099:Liver / Q000502:physiology*; D008107:Liver Diseases / Q000503:physiopathology*; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000502:physiology* / Q000627:therapeutic use
D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase