S-adenosylmethionine in Liver Health, Injury, and Cancer

Physiological Reviews (Impact Factor: 27.32). 10/2012; 92(4):1515-42. DOI: 10.1152/physrev.00047.2011
Source: PubMed


S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.

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    • "SAMe, upon transfer of its activated methyl group to an acceptor molecule such as glycine, is converted to Sadenosylhomocysteine (SAH)[7]. Glycine N-methyltransferase (GNMT) is one of the key enzymes involved in methionine and SAMe metabolism[8], and it has been proposed that GNMT maintains intracellular concentrations of SAMe within a narrow range[9]. There are several genetic conditions that lead to abnormally elevated plasma concentrations of methionine and SAMe that have been related with liver steatosis, such as GNMT, S-adenosylhomocysteine hydrolase and cystathionine β-synthase deficiency[10]. "
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    ABSTRACT: Background & aims: Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe NAFLD. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. Methods: We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. Results: We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and Methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameloriated liver steatosis. Conclusions: These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.
    Journal of Hepatology 09/2015; DOI:10.1016/j.jhep.2015.08.037 · 11.34 Impact Factor
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    • "Clinical efficacy of SAM in depression, osteoarthritis and liver diseases was demonstrated in dozens of studies summarized in the report, which searched through 25 biomedical databases (Hardy et al., 2003; Lu and Mato, 2012). There is extensive in vitro evidence that SAM suppress both growth and invasion in highly invasive cell lines (Pakneshan et al., 2004; Shukeir et al., 2006). "
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    ABSTRACT: One of the hallmarks of cancer is aberrant DNA methylation which is associated with abnormal gene expression. Both hypermethylation and silencing of tumor suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. Since DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumor suppressor genes. Two cytosine analogs, 5-azacytidine (5-azaC) (Vidaza) and 5-aza-2'-deoxycytidine (5-azadC), have been approved by FDA as antitumor agents in 2004 and 2006 respectively. However these agents might cause activation of a panel of prometastatic genes in addition to activating tumor suppressor genes which might lead to increased metastasis. This poses the challenge of how to target tumor suppressor genes and block cancer growth with DNA demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead.
    British Journal of Pharmacology 08/2014; 172(11). DOI:10.1111/bph.12885 · 4.84 Impact Factor
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    • "Indeed, the hydrophobic character of methionine is important for the binding of initiator tRNA to eIF-2, and most methionine residues are detected in the hydrophobic interior core of globular proteins [[3],[4]]. Previous studies have also shown that methionine is a source of the methyl groups that regulate the methylation of DNA and histones, and influence chromatin structure and gene expression in the liver [[5],[6]]. Methylation imbalance is correlated with several diseases including liver disease, cardiovascular disease and cancer [[7],[8]]. Methionine residues on the protein surface also function as endogenous antioxidants [[9],[10]]. "
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    ABSTRACT: Background Methionine, an essential amino acid, is required for protein synthesis and normal cell metabolism. The transmethylation pathway and methionine salvage pathway (MTA cycle) are two major pathways regulating methionine metabolism. Recently, methionine has been reported to play a key role in Drosophila fecundityResultsHere, we revealed that the MTA cycle plays a crucial role in Drosophila fecundity using the mutant of aci-reductone dioxygenase 1 (DADI1), an enzyme in the MTA cycle. In dietary restriction condition, the egg production of adi1 mutant flies was reduced compared to that of control flies. This fecundity defect in mutant flies was rescued by reintroduction of Dadi1 gene. Moreover, a functional homolog of human ADI1 also recovered the reproduction defect, in which the enzymatic activity of human ADI1 is required for normal fecundity. Importantly, methionine supply rescued the fecundity defect in Dadi1 mutant flies. The detailed analysis of Dadi1 mutant ovaries revealed a dramatic change in the levels of methionine metabolism. In addition, we found that three compounds namely, methionine, SAM and Methionine sulfoxide, respectively, may be required for normal fecundityConclusions In summary, these results suggest that ADI1, an MTA cycle enzyme, affects fly fecundity through the regulation of methionine metabolism.
    Journal of Biomedical Science 07/2014; 21(1):64. DOI:10.1186/s12929-014-0064-4 · 2.76 Impact Factor
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