Docosahexaenoic acid in plasma phosphatidylcholine may be a potential marker for in vivo phosphatidylethanolamine N-methyltransferase activity in humans.

BACKGROUND Choline is an essential nutrient for humans, and part of this requirement is met by endogenous synthesis catalyzed by hepatic phosphatidylethanolamine N-methyltransferase (PEMT). PEMT activity is difficult to estimate in humans because it requires a liver biopsy. Previously, we showed that mice that lack functional PEMT have dramatically reduced concentrations of docosahexaenoic acid (DHA; 22:6n-3) in plasma and of liver phosphatidylcholine (PtdCho)-a phospholipid formed by PEMT. OBJECTIVE The objective was to evaluate plasma PtdCho-DHA concentrations as a noninvasive marker of liver PEMT activity in humans. DESIGN Plasma PtdCho-DHA concentrations were measured in 72 humans before and after they consumed a low-choline diet, and correlations were analyzed in relation to estrogen status, PEMT polymorphism rs12325817, the ratio of plasma S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy), and dietary choline intake; all of these factors are associated with changes in liver PEMT activity. PtdCho-DHA and PEMT activity were also measured in human liver specimens. RESULTS At baseline, the portion of PtdCho species containing DHA (pmol PtdCho-DHA/nmol PtdCho) was higher in premenopausal women than in men and postmenopausal women (P < 0.01). This ratio was lower in premenopausal women with the rs12325817 polymorphism in the PEMT gene (P < 0.05), and PtdCho-DHA concentration and PEMT activity were lower in human liver samples from women who were homozygous for PEMT rs12325817 (P < 0.05). The ratio of DHA-PtdCho to PtdCho in plasma was directly correlated with the ratio of AdoMet to AdoHcy (P = 0.0001). The portion of PtdCho species containing DHA in plasma was altered in subjects who consumed a low-choline diet. CONCLUSION PtdCho-DHA may be useful as a surrogate marker for in vivo hepatic PEMT activity in humans. This trial was registered at clinicaltrials.gov as NCT00065546.

[1]  M. Milburn,et al.  Plasma metabolomic profile in nonalcoholic fatty liver disease. , 2011, Metabolism: clinical and experimental.

[2]  J. Galanko,et al.  Aberrant Estrogen Regulation of PEMT Results in Choline Deficiency-associated Liver Dysfunction* , 2010, The Journal of Biological Chemistry.

[3]  J. Galanko,et al.  Dietary choline requirements of women: effects of estrogen and genetic variation. , 2010, The American journal of clinical nutrition.

[4]  K. Costa,et al.  Phosphatidylethanolamine N‐methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  S. Zeisel,et al.  Sex and menopausal status influence human dietary requirements for the nutrient choline. , 2007, The American journal of clinical nutrition.

[6]  S. Zeisel.  Choline: critical role during fetal development and dietary requirements in adults. , 2006, Annual review of nutrition.

[7]  K. Costa,et al.  The FASEB Journal • Research Communication Common , 2022 .

[8]  M. Kohlmeier,et al.  Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Shuli Wang,et al.  Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD) , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  S. Zeisel,et al.  Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. , 2005, The Journal of nutrition.

[11]  S. Zeisel,et al.  Choline- and betaine-defined diets for use in clinical research and for the management of trimethylaminuria. , 2004, Journal of the American Dietetic Association.

[12]  M. Badea,et al.  Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. , 2004, The American journal of clinical nutrition.

[13]  S. Watkins,et al.  Phosphatidylethanolamine-N-methyltransferase activity and dietary choline regulate liver-plasma lipid flux and essential fatty acid metabolism in mice. , 2003, The Journal of nutrition.

[14]  S. Zeisel,et al.  Erratum: Concentrations of choline-containing compounds and betaine in common foods (Journal of Nutrition (2003) 133 (1302-1307)) , 2003 .

[15]  D. Vance,et al.  Molecular Dissection of the S-Adenosylmethionine-binding Site of Phosphatidylethanolamine N-Methyltransferase* , 2003, Journal of Biological Chemistry.

[16]  D. Vance,et al.  A Gender-specific Role For Phosphatidylethanolamine N-Methyltransferase-derived Phosphatidylcholine in the Regulation of Plasma High Density and Very Low Density Lipoproteins in Mice* , 2003, Journal of Biological Chemistry.

[17]  S. Zeisel,et al.  Concentrations of choline-containing compounds and betaine in common foods. , 2003, The Journal of nutrition.

[18]  D. Vance,et al.  An Unexpected Requirement for PhosphatidylethanolamineN-Methyltransferase in the Secretion of Very Low Density Lipoproteins* , 2002, The Journal of Biological Chemistry.

[19]  C. Takiya,et al.  Phosphatidylethanolamine N-methyltransferase activity is increased in rat intestinal brush-border membrane by chronic ethanol ingestion. , 2002, Alcohol and alcoholism.

[20]  J. Swenberg,et al.  Quantitation of choline and its metabolites in tissues and foods by liquid chromatography/electrospray ionization-isotope dilution mass spectrometry. , 2002, Analytical chemistry.

[21]  A. Sekine,et al.  Identification of 197 genetic variations in six human methyltransferase genes in the Japanese population , 2001, Journal of Human Genetics.

[22]  A. A. Spector,et al.  Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain , 2001, Journal of Molecular Neuroscience.

[23]  Michael J. Thomas,et al.  Molecular Distinction of Phosphatidylcholine Synthesis between the CDP-Choline Pathway and Phosphatidylethanolamine Methylation Pathway* , 1999, The Journal of Biological Chemistry.

[24]  C. Wagner,et al.  Measurement of plasma S-adenosylmethionine and S-adenosylhomocysteine as their fluorescent isoindoles. , 1998, Analytical biochemistry.

[25]  D. Vance,et al.  Phosphatidylethanolamine N-methyltransferase from liver. , 1997, Biochimica et biophysica acta.

[26]  J. Hansen,et al.  Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. , 1997, The American journal of clinical nutrition.

[27]  K. Suzuki,et al.  Bezafibrate and clofibric acid are novel inhibitors of phosphatidylcholine synthesis via the methylation of phosphatidylethanolamine. , 1996, Biochimica et biophysica acta.

[28]  K. Suzuki,et al.  The role of phosphatidylethanolamine methylation in the secretion of very low density lipoproteins by cultured rat hepatocytes: rapid inhibition of phosphatidylethanolamine methylation by bezafibrate increases the density of apolipoprotein B48-containing lipoproteins. , 1996, Biochimica et biophysica acta.

[29]  D. Vance,et al.  Expression of Phosphatidylethanolamine N-Methyltransferase-2 Is Markedly Enhanced in Long Term Choline-deficient Rats (*) , 1996, The Journal of Biological Chemistry.

[30]  J. Vance.  Secretion of VLDL, but not HDL, by rat hepatocytes is inhibited by the ethanolamine analogue N-monomethylethanolamine. , 1991, Journal of lipid research.

[31]  S. Zeisel,et al.  Effect of choline deficiency on S-adenosylmethionine and methionine concentrations in rat liver. , 1989, The Biochemical journal.

[32]  D. Vance,et al.  Kinetic mechanism of phosphatidylethanolamine N-methyltransferase. , 1988, The Journal of biological chemistry.

[33]  R. Wurtman,et al.  Rat Brain Phosphatidyl‐N,N‐Dimethylethanolamine Is Rich in Polyunsaturated Fatty Acids , 1985, Journal of neurochemistry.

[34]  D. Hoffman,et al.  Effects of a methyl-deficient diet on rat liver phosphatidylcholine biosynthesis. , 1981, Canadian journal of biochemistry.

[35]  D. Vance,et al.  Effect of diethylstilboestrol on phosphatidylcholine biosynthesis in the liver of roosters. , 1981, Biochemical Society transactions.

[36]  D L Young,et al.  Estradiol- and testosterone-induced alterations in phosphatidylcholine and triglyceride synthesis in hepatic endoplasmic reticulum. , 1971, Journal of lipid research.

[37]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[38]  M. Brosnan,et al.  Is it time to reevaluate methyl balance in humans? , 2006, The American journal of clinical nutrition.

[39]  D. Vance,et al.  Choline deficiency-induced liver damage is reversible in Pemt(-/-) mice. , 2002, The Journal of nutrition.

[40]  C. Lieber.  Alcoholic liver injury: pathogenesis and therapy in 2001. , 2001, Pathologie-biologie.

[41]  D. Vance,et al.  Metabolism of molecular species of phosphatidylethanolamine and phosphatidylcholine in rat hepatocytes during prolonged inhibition of phosphatidylethanolamine N-methyltransferase. , 1993, Journal of lipid research.