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

ABSTRACT: 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.The objective was to evaluate plasma PtdCho-DHA concentrations as a noninvasive marker of liver PEMT activity in humans.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.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.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.

SUBMITTER: da Costa KA

PROVIDER: S-EPMC3076652 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

da Costa Kerry-Ann KA Sanders Lisa M LM Fischer Leslie M LM Zeisel Steven H SH

The American journal of clinical nutrition 20110316 5

<h4>Background</h4>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 PE ...[more]

PMID: 21411618

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Project description:BackgroundLaryngeal cancer (LaC) remains one of the most common tumors of the respiratory tract with higher incidence in men than in women. The larynx is a small but vital organ on the neck. The dysfunction of the larynx can cause serious health problems such as hoarseness, respiratory distress, and dysphonia. Many lipids (e.g. phospholipid, cholesterol, fatty acid) have been recognized as a crucial role in tumorigenesis. However, the lipid biomarkers are lacking and the lipid molecular pathogenesis of LaC is still unclear.MethodsThis study aims to identify new LaC-related lipid biomarkers used for the diagnosis or early diagnosis of LaC and to uncover their molecular characteristics. Thus, we conducted serum and tissue nontargeted lipidomics study from LaC patients (n = 29) and normal controls (NC) (n = 36) via ultra-high performance liquid chromatography (UHPLC) coupled with high resolution mass spectrometry (HRMS). Multivariate and univariate statistics analyses were used to discriminate LaC patients from NC.ResultsAs expected, a lipid panel including LPC (16:0) and PE (18:0p_20:4) was defined to distinguish the LaC patients from healthy individuals with very high diagnosis performance (area under the curve (AUC) value = 1.000, sensitivity value = 1.000, and specificity value = 1.000). In addition, the levels of Cer, CerG1, SM, PC, PC-O, PE, PI, PS, and ChE in the LaC group significantly increased as compared with the NC group. However, the levels of LPC, LPC-O, LPE, LPE-p, and DG in the LaC group significantly deceased when the one was compared with the NC group. Among significantly changed lipid species, lysophospholipids containing a palmitoyl chain or an arachidonic acid acyl chain remarkably decreased and phospholipids including a palmitoyl chain or an arachidonic acid acyl chain increased in the LaC patients.ConclusionOur results not only indicate that lipidomics is powerful tool to explore abnormal lipid metabolism for the laC, but suggest that lysophospholipids and phospholipids may serve as potential biomarkers for diagnosis of LaC.

Project description:BackgroundPlasmalogens are either phosphatidylcholine (PC P) or phosphatidylethanolamine (PE P) glycerophospholipids containing a vinyl ether moiety in sn-1-position and an esterified fatty acid in sn-2 position. Multiple functions have been proposed, including reservoir of precursors for inflammatory mediators, modulation of membrane fluidity, and anti-oxidative properties. They could therefore play a role under conditions of metabolic stress. Especially enzymatically modified LDL (eLDL) and oxidatively modified LDL (oxLDL) represent modifications of LDL that are taken up by macrophages in atherosclerotic plaques. The aim of this study was to analyze plasmalogen related effects of eLDL and oxLDL in human monocyte derived macrophages, as well as the effects of HDL3 mediated deloading.MethodsElutriated monocytes from nine healthy donors were differentiated in vitro for four days. Macrophages were then loaded with native LDL, eLDL and oxLDL for 24h and subsequently deloaded with HDL3 for another 24h. Lipidomic and transcriptomic profiles were obtained.ResultsLoading of macrophages with eLDL and oxLDL led to a transient but strong elevation of lysophosphatidylcholine (LPC) most likely through direct uptake. Only eLDL induced increased levels of total PC, presumably through an induction of PC synthesis. On the other hand treatment with oxLDL led to a significant increase in PC P. Analysis of individual lipid species showed lipoprotein and saturation specific effects for LPC, PC P and PE P species. Membrane fluidity was decreased by the large amount of FC contained in the lipoproteins, as indicated by a lower PC to FC ratio after lipoprotein loading. In contrast the observed changes in the saturated to mono-unsaturated fatty acid (SFA to MUFA) and saturated to poly-unsaturated fatty acid (SFA to PUFA) ratios in PE P could represent a cellular reaction to counteract this effect by producing more fluid membranes. Transcriptomic analysis showed considerable differences between eLDL and oxLDL treated macrophages. As a common feature of both lipoproteins we detected a strong downregulation of pathways for endogenous lipid synthesis as well as for exogenous lipid uptake. Deloading with HDL3 had only minor effects on total lipid class as well as on individual lipid species levels, most of the time not reaching significance. Interestingly treatment with HDL3 had no effect on membrane fluidity under these conditions, although incubation with HDL3 was partially able to counteract the oxLDL induced transcriptomic effects. To investigate the functional effect of lipoprotein treatment on macrophage polarization we performed surface marker flow cytometry. Under our experimental conditions oxLDL was able to partially shift the surface marker pattern towards a pro-inflammatory M1-like phenotype. This is consistent with the consumption of arachidonic acid containing PE P species in oxLDL treated cells, presumably for the synthesis of inflammatory mediators.SummaryOur findings provide novel data on the lipoprotein induced, lipidomic and transcriptomic changes in macrophages. This can help us better understand the development of metabolic, inflammatory diseases as well as improve our background knowledge on lipid biomarkers in serum.

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

Publications

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

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