Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis


  • See Editorial on Page 1207

  • Potential conflict of interest: Nothing to report.

  • Supported by NIH RO1AT1576, RO1AT004896 (M.L.M-C., S.C.L., J.M.M.), RO1DK051719 (S.C.L., J.M.M.), R01DK080010, R01DK15289 (C.W.), Spanish Plan Nacional I+D SAF 2011-29851 (J.M.M.), ETORTEK-2010 Gobierno Vasco (P.A., M.L.M.-C, J.M.M.), PI11/01588, Sanidad Gobierno Vasco 2008, Educación Gobierno Vasco 2011 (M.L.M.-C), 2012 (J.M.M.), Sanidad Gobierno Vasco 2012 (M.V.R.), Basque Goverment IT-336-10 (to P.A. and X.B.), Saiotek S-PE11UN033 (P.A.), BBVA Foundation (to J.M.M., R.H.F.). Ciberehd is funded by ISCiii.

Address reprint requests to: José M Mato, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain. E-mail: director@cicbiogune.es; fax: +34-944-0611301.


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. (Hepatology 2013;58:1296–1305)