We also propose that the excess PC thus generated is catabolized, leading to TG synthesis and steatosis by way of diglyceride (DG) generation. We observed that Gnmt−/− mice Smoothened Agonist supplier present with normal hepatic lipogenesis and increased TG release. We also observed that the flux from PE to PC is stimulated in the liver of Gnmt−/− mice and that this results in a reduction in PE content and a marked increase in DG and TG. Conversely, reduction of hepatic SAMe following the administration of a methionine-deficient diet reverted the flux from PE to PC of Gnmt−/− mice to that of

wildtype animals and normalized DG and TG content preventing the development of steatosis. Gnmt−/− mice with an additional deletion of perilipin2, the predominant lipid droplet protein, maintain high SAMe levels, with a concurrent increased flux from PE to PC, but do not develop liver steatosis. Conclusion: These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration. (Hepatology 2013;58:1296–1305) find more Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries,[1] frequently being associated with obesity, dyslipidemia, and insulin resistance, a group of disorders that constitute the metabolic syndrome.[2] Although these aforementioned

conditions predispose the individual to develop NAFLD, our understanding of the mechanisms by which fat accumulates in the liver is not fully understood. Decreased content of S-adenosylmethionine (SAMe),

the major 上海皓元 biological methyl donor, has been linked to the development of NAFLD in different experimental models of steatosis in rodents and in humans.[3] For instance, deletion of methionine adenosyltransferase 1A (Mat1a), the principal gene involved in hepatic SAMe biosynthesis,[3] leads to a chronic reduction in liver SAMe level and to the spontaneous development of NAFLD.[4] The mechanisms linking SAMe with lipid homeostasis are not obvious at first glance. However, two recent publications have shed light on this process by showing: (1) that low hepatic SAMe reduces phosphatidylcholine (PC) content, leading to SREBP-1 activation and lipogenesis[5]; and (2) that low liver SAMe disrupts very low density lipoprotein (VLDL) assembly, leading to the synthesis of small, lipid-poor VLDL particles, and to a decrease in the secretion of triglycerides (TG).[6] The antisteatotic theory of SAMe has been challenged by the observation that deletion in mice of glycine N-methyltransferase (Gnmt), the main enzyme involved in hepatic SAMe catabolism,[7] results in a marked increase in hepatic SAMe content and rapid NAFLD development.[8] The Gnmt−/− mice show elevated serum aminotransferases at both 3 and 8 months of age. Histological examination of the livers of 3-month-old mutant mice showed steatosis and fibrosis, which were more pronounced in the livers of 8-month-old animals.