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Choline Metabolism and the Phosphatidylethanolamine N-Methyltransferase (PEMT) Pathway in Newborn Preterm Infants

Presented at the Neonatal Society 2013 Summer Meeting (programme).

Goss KCW1,2,3, Goss VM1,2, Townsend JP1, Gunda R3, Rhodes-Kitson J1, Thwaites R4, Clark HW1,2,3, Postle AD1,2

1 Southampton Centre for Biomedical Research, NIHR Respiratory Biomedical Research Unit, Southampton, UK
2 Division of Clinical Experimental Science, Faculty of Medicine, University of Southampton, Southampton, UK
3 Princess Anne Hospital, Southampton, UK
3 Queen Alexandra Hospital, Portsmouth, UK

Background: In adults the essential nutrient choline is important as a substrate for the production of phosphatidylcholine (PC) phospholipids and as a significant methyl donor. Previous studies have shown that the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, located specifically within hepatocytes, synthesises predominantly polyunsaturated PC species (1) and can produce choline de novo (2). To date the role of this pathway and the metabolism of this important substrate has not been investigated in the preterm infant.

Methods: Newborn premature infants (≤28+6 weeks) were recruited within 48 hours of birth. Lipid extracts from sequential plasma samples were then analysed by tandem electrospray ionization mass spectrometry (ESI MS/MS) and liquid chromatography multiple reaction monitoring tandem mass spectrometry (LC-MRM MS/MS) to monitor the incorporation of a short single IV infusion of methyl-D9 labelled choline (D9C) into the plasma choline pool and the phosphatidylcholine (PC) species. The incorporation into newly synthesized PC molecular species can then be monitored over time and directly reflects in vivo synthesis and secretion. (Local REC approval 09/H0502/95)

Results: In this study population the enrichment of choline by D9C in plasma decreases rapidly over the first 24 hours following infusion. The newly synthesised phospholipids produced via the PEMT pathway are predominantly mono- (PC16:0/18:1) and di-unsaturated (PC16:0/18:2) species but the pathway remains an important source of polyunsaturated PC species. Using multiple isotopomer distribution analysis (MIDA) the maximal synthetic rate of flux through the PEMT pathway is calculated to be 0.06%, significantly lower than reported in adult volunteers (0.53%). For the first time this study demonstrates that the activity of the hepatic PEMT pathway is significantly reduced when compared to adults despite rapid choline metabolism.

Conclusion: PEMT is vital as a source of de novo choline production and for the polyunsaturated phospholipid species. This study demonstrates for the first time that preterm infants are especially vulnerable to inadequate choline intake or deficiency and may have implications for recommended levels of choline supplementation in this population.

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1. PYNN, C.J., et al. 2011. Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo. J Lipid Res, 52, 399-407
2. JACOBS, R., et al. 2010. Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity. J Biol Chem, 285, 22403-13

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