Role of S‐adenosyl‐L‐methionine in liver health and injury†

Abstract

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. (HEPATOLOGY 2007;45: 1306-1312.)

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

“…50 The therapeutic benefit of AdoMet has been shown in the treatment of patients with intrahepatic cholestasis. 49 Our results agree with the above-mentioned studies and suggest that BHMT and MAT may constitute hitherto unrecognized targets of nitrosative stress in cholestatic liver injury.…”

“…48 The impairment of MAT function has been related to several liver conditions, such as cirrhosis, nonalcoholic steatohepatitis and hepatocellular carcinoma, and may contribute to liver disease pathogenesis. 49 States of increased NO production, such as septic shock or hypoxia, induce MAT inactivation without affecting MAT gene expression. 50 In fact, the S-nitrosation of hepatic MAT has been shown in vitro and in vivo, with the modification of Cys121 residue resulting in enzyme inactivation.…”

Comprehensive and quantitative proteome profiling of the mouse liver and plasma

“…These genetically engineered mouse models of human diseases have been shown to be helpful for understanding human disease progression. 12,13 They are also helpful for minimizing background genetic variations between target and control samples, making them attractive for studies aimed at discovering novel diagnostics and therapeutics. A comprehensive understanding of the mouse liver and plasma proteomes is critical for studies using mouse models aimed at identifying protein markers of liver diseases.…”

5-Aza-2'-deoxycytidine Induces Hepatoma Cell Apoptosis via Enhancing Methionine Adenosyltransferase 1A Expression and Inducing S-Adenosylmethionine Production

“…SAMe can regulate hepatocyte growth and apoptosis (Mato et al, 2007;Lu et al, 2008). Exogenous SAMe inhibits the growth of hepatoma cells and prevents development of HCC (Cai et al, 1998;Martínez-Chantar et al, 2006;Lu et al, 2009).…”