Metabolism may be defined as the totality of chemical reactions that can take place in a cell or an organism at a given instant; i.e., is not time invariant. This raises the question of metabolic control; that is, what factors control metabolism. The human metabolome contains more than 18,000 enzymatic reactions connecting over 114,000 metabolites. At first glance, the identification of the factors controlling the myriad of enzymatic reactions that configure the human metabolism poses an unapproachable complexity. However, investigations into the metabolism of a wide variety of organisms have shown that there is an extraordinary order and simplicity in the metabolic architecture in spite of an equally extraordinary diversity and individuality of metabolites consumed and produced. One of the main unifying and simplifying findings of metabolism was the discovery, in the first half of the 20th century, of central carbon metabolism; i.e., the oxidation of the characteristic molecules of each particular foodstuff (carbohydrates, fats, and proteins) producing a restricted group of products and liberating in the process the available energy. By far and away, the most common products of catabolism are acetyl-CoA, NAD(P)H, and ATP. These three metabolites and a handful of others, such as S-adenosylmethionine (SAMe), enable a diverse set of essential group transfer reactions that power metabolism. SAMe, after ATP, may be the most common metabolite used for group transfer reactions. SAMe is the source of essentially all the hundreds of millions of daily methyl transfer reactions in a cell. This massive drain of SAMe imposes a tight control in its synthesis. We have shown that a decrease in hepatic SAMe affects DNA methylation and transcriptomics, then proteomics and post-translational modifications, and finally a broader reach of metabolomics throughout the organ, leading to steatohepatitis, fibrosis and liver cancer. Our studies also indicate that around half of the patients with steatohepatitis and the majority, if not all, of the patients with liver cirrhosis, have a net deficiency in SAMe; and that SAMe treatment reduces mortality in patients with alcoholic liver cirrhosis.


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