Plasma Homocysteine Is Regulated by Phospholipid Methylation

Abstract

Mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine, a nonprotein amino acid, is formed from S-adenosylhomocysteine and partially secreted into plasma. A potential source for homocysteine is methylation of the lipid phosphatidylethanolamine to phosphatidylcholine by phosphatidylethanolamine N-methyltransferase in the liver. We show that mice that lack phosphatidylethanolamine N-methyltransferase have plasma levels of homocysteine that are ϳ50% of those in wild-type mice. Hepatocytes isolated from methyltransferase-deficient mice secrete ϳ50% less homocysteine. Rat hepatoma cells transfected with phosphatidylethanolamine N-methyltransferase secrete more homocysteine than wild-type cells. Thus, phosphatidylethanolamine N-methyltransferase is an important source of plasma homocysteine and a potential therapeutic target for hyperhomocysteinemia.Mild hyperhomocysteinemia is an independent risk factor for cardiovascular (1, 2) and atherosclerotic disease (3). Total plasma homocysteine (Hcy) 1 values of ϳ10 M for men and ϳ8 M for women are in the normal range. However, even a small increase (ϳ5 M) in total plasma Hcy is associated with a 60% increased risk of coronary artery disease for men and 80% for women (3). Moreover, a number of studies have demonstrated that smoking, excessive drinking of alcohol, obesity, type II diabetes, and an unhealthy diet contribute to mild hyperhomocysteinemia (1, 2). In addition, elevated plasma Hcy has recently been linked to Alzheimer's disease and cognitive impairment in the elderly (4, 5).Hcy is a non-protein amino acid derived from the catabolism of S-adenosylhomocysteine (AdoHcy), an immediate product of trans-methylation reactions that utilize S-adenosylmethionine (AdoMet) (6). Hcy has three possible fates: 1) methylation to methionine with N-5-methyltetrahydrofolate or betaine as the methyl donor, 2) conversion to cysteine via the trans-sulfuration pathway, and 3) release into extracellular fluids (e.g. plasma and urine). AdoMet-dependent methyltransferases catalyze many critical reactions including methylation of RNA, DNA, proteins, and small molecules such as guanidinoacetate and glycine (6). The potential of methyltransferases to regulate plasma Hcy is not well defined.Phosphatidylethanolamine N-methyltransferase (PEMT) is a liver-specific enzyme that generates AdoHcy during the conversion of one membrane lipid, phosphatidylethanolamine, into another membrane lipid, phosphatidylcholine (PC) (7). PEMT accounts for the formation of ϳ30% PC made in liver (8, 9). With this large capacity for PC synthesis and the generation of three AdoHcy molecules for each PC molecule synthesized, we hypothesized that the PEMT reaction might contribute significantly to Hcy in plasma. We have utilized the Pemt Ϫ/Ϫ mouse, hepatocytes derived from these mice, and overexpression of PEMT in McArdle RH7777 (rat hepatoma) cells to test this hypothesis. The results show that PEMT expression enhances plasma Hcy levels and the secretion of Hcy from hepatocyte...

Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology

“…Moreover, hepatocytes isolated from Pemt Ϫ/Ϫ mice secreted less Hcy into the medium than did hepatocytes from littermate controls. Because PEMT deficiency does not change the levels of enzymes involved in metabolizing Hcy and because the levels of hepatic AdoMet and AdoHcy were unaltered, we concluded that PEMT activity directly regulates plasma Hcy levels (45).…”

“…Reconstitution of PEMT activity in McArdle cells stimulated Hcy secretion into the medium compared with vector-transfected cells (45). Mutagenesis of lysine 197 in the C-terminal ER retrieval motif of PEMT resulted in re-localization of PEMT from the ER to the Golgi.…”

“…Because PEMT accounts for the formation of 30% PC made in the liver and 3 AdoHcy molecules are synthesized for every PC molecule generated, we hypothesized that PEMT might contribute significantly to plasma Hcy. Remarkably, deletion of PEMT decreased circulating Hcy by 50% (45). Moreover, hepatocytes isolated from Pemt Ϫ/Ϫ mice secreted less Hcy into the medium than did hepatocytes from littermate controls.…”

Effect of High Methionine and Folic Acid Diet on The Level of Homocysteine and Lipid Profile in Experimental Rats

“…According to Preynat et al [2010], folic acid per se or together with vitamin B 12 shows a tendency towards increasing the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) [Preynat et al, 2010]. About 50% of the plasma Hcy is involved in PC synthesis in the liver [Noga et al, 2003]; therefore, PC synthesis is recognized as a contact point between SAM and phospholipid metabolisms [Obeid & Herrmann, 2009]. …”

Suplementação De Creatina, Homocisteína E Estresse Oxidativo

“…Entretanto, tais dados não podem ser fielmente reproduzidos em humanos. Ainda assim, autores apontam algumas controvérsias quanto aos clássicos estudos realizados por Mudd e Pole 36 e Mudd et al 37 e sugerem que a síntese de creatina pode não ser a maior responsável pelas reações de metiltransferases, apontando a biossíntese de fosfatidilcolina como importante determinante da demanda de metilação e consequentemente significante na produção de Hcy 56 . Além disso, estudos recentes têm demonstrado que outras importantes substân-cias podem modular o balanço de metilação e os ní-veis de Hcy como a betaína, glicina e serina 10,11 .…”