Biology subjects
Publications and source records attributed to Furse, S..
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Essential fatty acids (EFAs) and their derivatives, the long and very long chain polyunsaturated fatty acids (LC-PUFAs), are preferentially transported by the mother to the fetus. Failure to supply EFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary EFA intake and the molecular mechanisms of maternal supply. Here we combine untargeted lipidomics with transcriptional profiling of healthy and genetically-manipulated murine models to understand the maternal adaptations required to provide LC-PUFAs to the developing fetus. We discovered a late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway which dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduced LC-PUFA accumulation by the fetus. Overall our work suggests new molecular strategies for improving maternal-fetal transfer of these important lipids.
Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female heart lipidomes are more sensitive to maternal obesity than male fetuses; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.
The structural challenges faced by eukaryotic cells through the cell cycle are key for understanding cell viability and proliferation. In this study, we tested the hypothesis that the biosynthesis of structural lipids is linked to the cell cycle. If true, this would suggest that the cells structure would form part the control of the cell cycle. Lipidomics (31P NMR and MS), proteomics (Western immunoblotting) and transcriptomics (RT-qPCR) techniques were used to profile the lipid fraction and characterise aspects of its metabolism at seven stages of the cell cycle of the model eukaryote, Desmodesmus quadricauda. We found considerable, transient increases in the abundance of phosphatidylethanolamine during the G1 phase (+35%, ethanolamine phosphate cytidylyltransferase increased 2{middle dot}5x) and phosphatidylglycerol over the G1/pre-replication phase boundary (+100%, phosphatidylglycerol synthase increased 22x). The relative abundance of phosphatidylcholine fell by ~35% during the G1. N-Methyl transferases for the conversion of phosphatidylethanolamine into phosphatidylcholine were not found in the de novo transcriptome profile, though a choline phosphate transferase was found, suggesting that the Kennedy pathway is the principal route for the synthesis of PC. The fatty acid profiles of the four most abundant lipids suggested that these lipids were not generally converted between one another. The relative abundance of both phosphatidylinositol and its synthase remained constant despite an eightfold increase in cell volume. We conclude that the biosynthesis of the three most abundant structural phospholipids is linked to the cell cycle in D. quadricauda.
While the consequences of poor maternal diet on the offspring’s cardio-metabolic health have been studied in detail, the role of the father’s diet on the health of his offspring is poorly understood. We used a known mouse model to establish the impact of an isocaloric paternal low-protein high-carbohydrate diet on the offspring’s lipid metabolism. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate male and female offspring, in serum, liver, brain, heart and abdominal adipose tissues by Mass Spectrometry and Nuclear Magnetic Resonance. Using a purpose-built computational tool for analysing lipid metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of alterations associated with paternal diet. These elucidate a mechanism for the defective physiological behaviour of systems at risk of cardio-metabolic disease.Competing Interest StatementThe authors have declared no competing interest.View Full Text
Dried blood spots (DBS) and dried milk spots (DMS) represent convenient matrices for collecting and storing human samples. However, the use of these sample types for researching lipid metabolism remains relatively poorly explored, and especially the efficiency of lipid extraction is unclear. A visual inspection of punched DBSs after standard extraction suggests that the samples remain largely intact. DMSs comprise a dense aggregate of milk fat globules on one side of the card, suggesting that the lipid fraction may be physically inaccessible. This led us to the hypotheses that decoagulating may facilitate lipid extraction from both DBSs and DMSs. We tested decoagulation using a mixture of strong chaeotropes (guanidine and thiourea) in both DBS and DMS in the context of high throughput lipidomics (96/384w plate). Extraction of lipids from DMSs was tested with established extractions and one novel solvent mixture in a high throughput format. We found that exposure of DBSs to chaeotropes facilitated collection of the lipid fraction but was ineffective for DMSs. The lipid fraction of DMSs was best isolated without water, using a mixture of xylene/methanol/isopropanol (1:2:4). We conclude that decoagulation is essential for efficient extraction of lipids from DBSs and that a non-aqueous procedure using a spectrum of solvents is the best procedure for extracting lipids from DMSs. These methods represent convenient steps that are compatible with the sample structure and type, and with high throughput lipidomics. HighlightsO_LIThe efficiency of lipid extractions on dried milk and dried blood spots was tested C_LIO_LIThe number of lipid variables and the total signal strength were used as objective measures C_LIO_LIDecoagulation of dried blood spots improved extraction efficiency C_LIO_LIA mixture of xylene, methanol and isopropanol isolates the lipid fraction best from DMSs C_LIO_LIAn aqueous extraction using dichloromethane was the most efficient method for isolating lipids from DBSs C_LI
Dysregulation of the biosynthesis of cholesterol and other lipids has been implicated in neurological diseases, including Parkinson's disease, where the misfolding of membraneassociated -Synuclein is a key molecular event. Recent research also suggests that -Synuclein aggregation is influenced by the lipid environment. The exact molecular mechanisms responsible for cholesterols effect on -Synuclein binding to lipids and how this binding may affect -Synuclein oligomerization and fibrillation remain elusive, as does the relative importance of cholesterol versus other lipid factors. We probed the interactions and fibrillation behaviour of -Synuclein using SMA nanodiscs, containing zwitterionic and anionic lipid model systems with and without cholesterol. SPR and ThT fluorescence assays were then employed to monitor -Synuclein binding, as well as fibrillation in the absence and presence of membrane models. 1H-15N correlated NMR was used to monitor the fold of -Synuclein in response to nanodisc binding, and we determined individual residue apparent affinities for the nanodisc-contained bilayers. Cholesterol inhibited -Synuclein interaction with lipid bilayers. We also find that cholesterol significantly promotes -Synuclein fibrillation, with a more than 20-fold reduction of lag-times before fibrillation onset. When -Synuclein-bilayer interactions were analysed for individual residues by solution-state NMR, we observed two different effects of cholesterol. In nanodiscs made of DOPC, cholesterol modulated the NAC part of -Synuclein, leading to stronger interaction of this region with the lipid bilayer. In contrast, in the nanodiscs comprising DOPC, DOPE and DOPG, the NAC part was mostly unaffected by cholesterol, while the binding of the N-terminal and the C-terminal were both inhibited.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC=\"FIGDIR/small/725762v3_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (54K):\norg.highwire.dtl.DTLVardef@1c9c126org.highwire.dtl.DTLVardef@a7e026org.highwire.dtl.DTLVardef@16d1a9forg.highwire.dtl.DTLVardef@1eeda2d_HPS_FORMAT_FIGEXP M_FIG C_FIG