Phosphatidylcholine’s functions beyond that of a membrane brick

Furse, Samuel; Kroon, Anton I.P.M. de

doi:10.3109/09687688.2015.1066894

Cited by 105 publications

(87 citation statements)

References 20 publications

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“…Of note, phosphatidylcholines (and lysophosphatidylcholines) represent by mass more than 76% of total glycerophospholipids in healthy volunteers [15]. Although phosphatidylcholines had been described as major phospholipids in lipoproteins and cellular membranes for a long time [16], several recent advances have expanded on the notion that PCs are not just a kind of cellular bricks [17]. Such new roles include gene regulation: PC 16:0/18:1 have been described as an endogenous ligand for the nuclear receptor PPAR alpha in hepatocytes [18], a transcription factor regulating the expression of many genes that govern lipid metabolism [19].…”

Section: Discussionmentioning

confidence: 99%

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

et al. 2017

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Metabolomic approaches are increasingly used to identify new disease biomarkers, yet normal values of many plasma metabolites remain poorly defined. The aim of this study was to define the “normal” metabolome in healthy volunteers. We included 800 French volunteers aged between 18 and 86, equally distributed according to sex, free of any medication and considered healthy on the basis of their medical history, clinical examination and standard laboratory tests. We quantified 185 plasma metabolites, including amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexose, using tandem mass spectrometry with the Biocrates AbsoluteIDQ p180 kit. Principal components analysis was applied to identify the main factors responsible for metabolome variability and orthogonal projection to latent structures analysis was employed to confirm the observed patterns and identify pattern-related metabolites. We established a plasma metabolite reference dataset for 144/185 metabolites. Total blood cholesterol, gender and age were identified as the principal factors explaining metabolome variability. High total blood cholesterol levels were associated with higher plasma sphingomyelins and phosphatidylcholines concentrations. Compared to women, men had higher concentrations of creatinine, branched-chain amino acids and lysophosphatidylcholines, and lower concentrations of sphingomyelins and phosphatidylcholines. Elderly healthy subjects had higher sphingomyelins and phosphatidylcholines plasma levels than young subjects. We established reference human metabolome values in a large and well-defined population of French healthy volunteers. This study provides an essential baseline for defining the “normal” metabolome and its main sources of variation.

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Section: Discussionmentioning

confidence: 99%

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

et al. 2017

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“…Also in breast cancer, CHKα activity has been described as the main regulator of the cholinic phenotype [22]. CHKα catalyzes the phosphorylation of free choline to PC during the synthesis of the membrane lipid phosphatidylcholine, thus CHKα is of highest importance for the integrity of the cell membrane and a variety of signaling pathways involving membrane lipids and membrane anchored proteins [39, 40]. As expected, direct suppression of CHKα through RNA-interference reduced the cholinic phenotype to levels similar or even lower than observed after ZEB1 suppression (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

et al. 2016

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Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy.

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“…PC is also metabolized to generate the second messengers, diacylglycerol (DAG) and phosphatidic acid, as well as arachidonic acid/prostaglandins/leukotrienes involved in inflammation and asthma , and the osmolyte glycerophosphocholine . In addition, specific fatty acyl species of PCs are essential components of pulmonary surfactant in lungs and as ligands for cellular receptors .…”

Section: Overview Of Phosphatidylcholine Structure and Functionmentioning

confidence: 99%

“…PPARs are nuclear receptors that regulate gene transcription that bind hydrophobic ligands. The 16:0/18:1 PC species appears to be the endogenous ligand for PPARα, which in turn regulates transcription of a plethora of lipid‐metabolizing enzymes . Indeed, hepatic portal vein injection of 16:0/18:1 PC into mice resulted in an increase in PPARα‐mediated gene expression and a decrease in hepatic steatosis.…”

Section: Roles Of Pc Acyl Chain Specificity In Cellular and Human Biomentioning

confidence: 99%

“…Indeed, hepatic portal vein injection of 16:0/18:1 PC into mice resulted in an increase in PPARα‐mediated gene expression and a decrease in hepatic steatosis. PPARδ controls gene expression for proteins required for fatty acid uptake and β‐oxidation by muscle, and it was determined to be bound by 18:0/18:1 PC and regulated by 18:0/18:1 PC serum level .…”

Section: Roles Of Pc Acyl Chain Specificity In Cellular and Human Biomentioning

confidence: 99%

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From yeast to humans – roles of the Kennedy pathway for phosphatidylcholine synthesis

McMaster

2017

FEBS Letters

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The major phospholipid present in most eukaryotic membranes is phosphatidylcholine (PC), comprising~50% of phospholipid content. PC metabolic pathways are highly conserved from yeast to humans. The main pathway for the synthesis of PC is the Kennedy (CDP-choline) pathway. In this pathway, choline is converted to phosphocholine by choline kinase, phosphocholine is metabolized to CDP-choline by the rate-determining enzyme for this pathway, CTP:phosphocholine cytidylyltransferase, and cholinephosphotransferase condenses CDP-choline with diacylglycerol to produce PC. This Review discusses how PC synthesis via the Kennedy pathway is regulated, its role in cellular and biological processes, as well as diseases known to be associated with defects in PC synthesis. Finally, we present the first model for the making of a membrane via PC synthesis.

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Phosphatidylcholine’s functions beyond that of a membrane brick

Cited by 105 publications

References 20 publications

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

From yeast to humans – roles of the Kennedy pathway for phosphatidylcholine synthesis

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