S-adenosylmethionine in Liver Health, Injury, and Cancer
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.
Available from: Juan J. Loor
- "Thus, it is not entirely surprising that supplementation of rumen-protected Met to lactating dairy cows confers beneficial effects on milk protein yield (Ordway et al., 2009), liver function, and antioxidant precursor synthesis (Osorio et al., 2014b). Due to the multiple biological processes that require SAM, including transsulfuration, polyamine biosynthesis , and DNA methylation (Lu and Mato, 2012), the requirement for methyl donors, such as choline and Met, increases at the onset of lactation (Preynat et al., 2009). The methylation of DNA regions is one of the epigenetic modifications involved in the "
[Show abstract] [Hide abstract]
ABSTRACT: The availability of Met in metabolizable protein (MP) of a wide range of diets for dairy cows is low. During late pregnancy and early lactation, in particular, suboptimal Met in MP limits its use for mammary and liver metabolism and also for the synthesis of S-adenosylmethionine, which is essential for many biological processes, including DNA methylation. The latter is an epigenetic modification involved in the regulation of gene expression, hence, tissue function. Thirty-nine
Holstein cows were fed throughout the peripartal period (−21 d to 30 d in milk) a basal control (CON) diet (n = 14) with no Met supplementation, CON plus MetaSmart (MS; Adisseo NA, Alpharetta, GA; n = 12), or CON plus Smartamine M (SM; Adisseo NA; n = 13). The total mixed ration dry matter for the close-up and lactation diets was measured weekly, then the Met supplements were adjusted daily and top-dressed over the total mixed ration at a rate of 0.19 (MS) or 0.07% (SM) on a dry matter basis. Liver tissue was collected on −10, 7, and 21 d for global DNA and peroxisome proliferator-activated receptor alpha (PPARα) promoter region-specific methylation. Several PPARα target and putative target genes associated with carnitine synthesis and uptake, fatty acid metabolism, hepatokines, and carbohydrate metabolism were also studied. Data were analyzed using PROC MIXED of SAS (SAS Institute Inc., Cary, NC) with the preplanned contrast CON versus
SM + MS. Global hepatic DNA methylation on d 21 postpartum was lower in Met-supplemented cows than CON. However, of 2 primers used encompassing 4 to 12 CpG sites in the promoter region of bovine PPARA, greater methylation occurred in the region encompassing −1,538 to −1,418 from the transcription start site in cows supplemented with Met. Overall expression of PPARA was greater in Met-supplemented cows than CON. Concomitantly, PPARA-target genes, such as
ANGPTL4, FGF21, and PCK1, were also upregulated overall by Met supplementation. The upregulation of PPARα target genes indicates that supplemental Met, likely through the synthesis of S-adenosylmethionine, activated PPARA-regulated signaling pathways. Upregulation of hepatic PPARA has been associated with improved lipid metabolism and immune function, both of which were reported in companion publications from this study. In turn, those positive effects resulted in improved postpartal health and performance. Further research is needed to study more closely the mechanistic connections between global DNA and promoter region specific PPARA methylation with PPARA expression and functional outcomes in liver.
Journal of Dairy Science 11/2015; 99. DOI:10.3168/jds.2015-10157 · 2.57 Impact Factor
Available from: Conrad Wagner
- "SAMe, upon transfer of its activated methyl group to an acceptor molecule such as glycine, is converted to Sadenosylhomocysteine (SAH). Glycine N-methyltransferase (GNMT) is one of the key enzymes involved in methionine and SAMe metabolism, and it has been proposed that GNMT maintains intracellular concentrations of SAMe within a narrow range. 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. "
[Show abstract] [Hide abstract]
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.
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.
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.
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
Available from: David Cheishvili
- "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). "
[Show abstract] [Hide abstract]
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
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.