Effects of a methyl-deficient diet on rat liver phosphatidylcholine biosynthesis

Abstract

To produce a severe choline-methionine deficiency, a synthetic L-amino acid diet, free of choline, methionine, vitamin B12, and folic acid and supplemented with guanidoacetic acid, a methyl group acceptor, was fed to female rats for 2 weeks. The in vitro activity of liver microsomal phosphatidylethanolamine methyltransferase was stimulated twofold when compared with basal diet controls. The activity of choline phosphotransferase was depressed by 86%; thus, the contribution of the methyltransferase in the overall synthesis of phosphatidylcholine apparently increased. However, measurement of the in vivo methylation of phosphatidylethanolamine by incorporation of [1,2-14C]ethanolamine into phosphatidylcholine indicates that the methylation pathway is markedly depressed in methyl deficiency. Hepatic concentrations of the methyltransferase substrate, S-adenosylmethionine, and the inhibitory metabolite, S-adenosylhomocysteine, were significantly altered such that an unfavorable environment for methylation was present in the deficient animal. The ratio of substrate to inhibitor was depressed from 5.2:1 in the controls to 1.7:1 in the livers of methyl-depleted rats. Control of transmethylation in accordance with the availability of substrates, phosphatidylethanolamine, or S-adenosylmethionine, and the level of S-adenosylhomocysteine is discussed.

Effect of choline deficiency on S-adenosylmethionine and methionine concentrations in rat liver

“…We suggest an alternative hypothesis, that choline deficiency resulted in an increased utilization of AdoMet. Choline deficiency increases the requirement for phosphatidylcholine synthesis via the sequential methylation of phosphatidylethanolamine [33][34][35]. The enzyme catalysing these reactions, phosphatidylethanolamine Nmethyltransferase (EC 2.1.1.17), uses AdoMet as the methyl donor [35,36], and choline deficiency does increase the utilization of AdoMet for phosphatidylcholine synthesis [33,37,38].…”

Choline Nutrition Programs Brain Development Via DNA and Histone Methylation

“…(2). This effect is explained by the direct relationship between dietary intake of choline (and/or other methyl groups) and tissue levels of AdoMet that is frequently observed [75][76][77][78][79][80][81][82]. This change results in altered phenotype governed by DNA methylation.…”

Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet

“…Under normal conditions, the PEMT pathway accounts for approximately 20-30% of PC synthesized in the liver [21][22][23]. With dietary choline restriction, however, nearly all hepatic PC is synthesized via the PEMT pathway, and PEMT expression is markedly upregulated [24][25][26]. In addition to its function as an alternative pathway for hepatic PC synthesis, PEMT has a significant role in lipid metabolism and homeostasis [29,30,32].…”

“…Under normal conditions the PEMT pathway accounts for 20-30% of the hepatic PC synthesis [21][22][23]. However, during choline deficient states, the PEMT pathway synthesizes essentially all of the hepatic PC [24][25][26]. In addition to its role in PC synthesis during choline deficient states, PEMT appears to have an important role in many physiologic processes, including lipid homeostasis and regulation of the cellular methylation status [27][28][29][30][31][32][33][34].…”