2010/03/18

Timing is everything

Current estimates by the World Health Organization indicate that, worldwide, about 1.6 billion (BMI >25 kg/m2) adults are overweight and 400 million are obese (BMI >30 kg/m2), and in developed countries with a westernized style of life about two-thirds of the adults are overweight or obese. Although the majority of these individuals may have fatty liver, luckily, only a small fraction of these will develop hepatocellular carcinoma (HCC). Nevertheless, hepatosteatosis, together with its more severe complication non-alcoholic steatohepatitis, classified as non-alcoholic fatty liver disease (NAFLD), might match hepatitis C virus infection as the major HCC risk factor.

But not only over-nutrition produces NAFLD, since this condition is also frequent in individuals suffering from essential nutrients deficiency. Charles Best was the first to realize that; in 1932 he observed that choline prevented the deposition of fat in the liver, a phenomenon known as "lipotropism". In a subsequent study carried out in 1937, Tucker and Eckstein discovered the lipotropic action of methionine. Then, in 1940 du Vigneaud described the synthesis of choline from methionine, a process known as "transmethylation". In 1953, Cantoni showed that in order to transfer its methyl group, methionine is first converted to S-adenosylmethionine (SAMe). The enzyme converting methionine into SAMe is called methionine adenosyltransferase (MAT).

The liver expresses two MAT genes, MAT1A and MAT2A. In contrast to non-proliferating (differentiated) hepatocytes, which rely primarily on MAT1A to generate SAMe and maintain methionine homeostasis, embryonic and proliferating adult hepatocytes as well as liver cancer cells instead rely on MAT2A to synthesize SAMe. The difference between these genes is that one, MAT1A, is more efficient metabolizing blood methionine and maintains higher hepatic SAMe levels than the other, MAT2A. This switch from MAT1A to MAT2A expression is critical for normal hepatocyte growth and is a proliferative advantage for hepatoma cells. Thus, mice lacking MAT1A spontaneously develop NAFLD and HCC despite having an increased expression of MAT2A.

Vázquez-Chantada et al. have recently produced some mechanistic insights into how this switch between MAT1A and MAT2A occurs. HuR is a RNA-binding protein that increases the half-life of target mRNAs, whereas AUF1 destabilizes target mRNAs. They observed that, under a variety of conditions, the switch from MAT1A to MAT2A coincides with an increase in HuR and AUF1 expression. They also found that HuR associates with MAT2A mRNA increasing its stability, while AUF1 associates with MAT1A mRNA decreasing its stability. Unexpectedly, authors discovered that methylated HuR destabilizes MAT2A, explaining why SAMe administration inhibits MAT2A expression. Understanding how HuR and AUF1 expression is regulated during NAFLD progression and hepatocarcinogenesis may identify potential points for therapeutic intervention.