Excess S‐adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis. Issue 4 (14th August 2013)

• Record Type: Journal Article
• Authors: Martínez‐Uña, Maite; Varela‐Rey, Marta; Cano, Ainara; Fernández‐Ares, Larraitz; Beraza, Naiara; Aurrekoetxea, Igor; Martínez‐Arranz, Ibon; García‐Rodríguez, Juan L.; Buqué, Xabier; Mestre, Daniela; Luka, Zigmund; Wagner, Conrad; Alonso, Cristina; Finnell, Richard H.; Lu, Shelly C.; Martínez‐Chantar, M. Luz; Aspichueta, Patricia; Mato, José M.
• Is Part Of: Hepatology. Volume 58:Issue 4(2013:Oct.)
• Page Start: 1296
• Page End: 1305
• Publication Date: 2013-08-14
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26399
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Methionine adenosyltransferase 1A (<italic>MAT1A</italic>) and glycine <italic>N</italic>‐methyltransferase (<italic>GNMT</italic>) are the primary genes involved in hepatic S‐adenosylmethionine (SAMe) synthesis and degradation, respectively. <italic>Mat1a</italic> ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. <italic>Gnmt</italic>‐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) <italic>N</italic>‐methyltransferase (PEMT) pathway is stimulated in <italic>Gnmt<sup>−/−</sup></italic> 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 <italic>Gnmt<sup>−/−</sup></italic> 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 <italic>Gnmt<sup>−/−</sup></italic> 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 <italic>Gnmt<sup>−/−</sup></italic> mice to that of wildtype animals and normalized DG and TG content preventing the development of steatosis. <italic>Gnmt<sup>−/−</sup></italic> 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. <italic>Conclusion</italic>: These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration. (H<sc>epatology</sc> 2013;58:1296–1305)</p> </abstract>