Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis.

Martínez-Uña M, Varela-Rey M, Cano A, Fernández-Ares L, Beraza N, Aurrekoetxea I, Martínez-Arranz I, García-Rodríguez JL, Buqué X, Mestre D, Luka Z, Wagner C, Alonso C, Finnell RH, Lu SC, Martínez-Chantar ML, Aspichueta P, Mato JM
Hepatology. 2013 58 (4): 1296-305

PMID: 23505042 · PMCID: PMC3720726 · DOI:10.1002/hep.26399

UNLABELLED - Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are the primary genes involved in hepatic S-adenosylmethionine (SAMe) synthesis and degradation, respectively. Mat1a ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. Gnmt-deficient mice, despite showing a large increase in hepatic SAMe, also develop steatosis. We hypothesized that as an adaptive response to hepatic SAMe accumulation, phosphatidylcholine (PC) synthesis by way of the phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is stimulated in Gnmt(-/-) mice. 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 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.

Copyright © 2013 by the American Association for the Study of Liver Diseases.

MeSH Terms (17)

Animals Disease Models, Animal Fatty Liver Female Glycine N-Methyltransferase Homeostasis Lipid Metabolism Liver Male Membrane Proteins Mice Mice, Knockout Perilipin-2 Phosphatidylcholines Phosphatidylethanolamines S-Adenosylmethionine Triglycerides

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