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Biochemistry Oct 2019Two 15 μs all-atom simulations of the A adenosine receptor were obtained in a ternary mixture of cholesterol, saturated phosphatidylcholine lipids, and unsaturated...
Two 15 μs all-atom simulations of the A adenosine receptor were obtained in a ternary mixture of cholesterol, saturated phosphatidylcholine lipids, and unsaturated phosphatidylcholine lipids. An analysis of local lipid solvation is reported on the basis of a Voronoi tessellation of the upper and lower leaflets, identifying first and second solvation shells. The local environments of both the inactive state and the partially active state of the receptor are significantly enriched with unsaturated chains but depleted of cholesterol and saturated chains, relative to the bulk membrane composition. In spite of the local depletion of cholesterol, the partially active receptor binds cholesterol at three locations during the entire simulation trajectory. These long-lived interactions represent the extreme of a very broad distribution of first-solvation shell lipid lifetimes, confounding sharp distinctions between lipid interactions. The broad distributions of lifetimes also make equilibrating the local lipid environment difficult, necessitating long simulation times.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Binding Sites; Cholesterol; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Molecular Dynamics Simulation; Phosphatidylcholines; Protein Structure, Secondary; Receptor, Adenosine A2A
PubMed: 31496229
DOI: 10.1021/acs.biochem.9b00607 -
Biointerphases Apr 2018Femtosecond laser desorption ionization mass spectrometry was used to obtain mass spectrometric (MS) images of lipids in human pancreatic tissue. The resulting MS images...
Femtosecond laser desorption ionization mass spectrometry was used to obtain mass spectrometric (MS) images of lipids in human pancreatic tissue. The resulting MS images were analyzed using multivariate analysis, specifically principal component analysis and maximum a posteriori (MAP) reconstruction. Both analysis methods showed that the MS images can be separated into lipid and non-lipid areas. MAP analysis further indicated that the lipid areas are composed of phosphatidylcholines and fatty acids. However, definitive identification of the lipids cannot be made because none of the intact parent ions of phosphatidylcholine, sphingomyelins, and/or other lipids were observed. The MAP analysis also revealed that the non-lipid areas could be separated into components that are due to the sample chemical treatment and topography.
Topics: Fatty Acids; Humans; Mass Spectrometry; Multivariate Analysis; Pancreas; Phosphatidylcholines
PubMed: 29609468
DOI: 10.1116/1.5016301 -
PLoS Medicine May 2005Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Betaine (trimethylglycine) lowers plasma homocysteine, a possible risk factor for cardiovascular disease. However, studies in renal patients and in obese individuals who are on a weight-loss diet suggest that betaine supplementation raises blood cholesterol; data in healthy individuals are lacking. Such an effect on cholesterol would counteract any favourable effect on homocysteine. We therefore investigated the effect of betaine, of its precursor choline in the form of phosphatidylcholine, and of the classical homocysteine-lowering vitamin folic acid on blood lipid concentrations in healthy humans.
METHODS AND FINDINGS
We measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations. We combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25-0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04-0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14-0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/d also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/d of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/l (0.06-0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/d) had no effect on lipid concentrations.
CONCLUSIONS
Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering. In our study phosphatidylcholine supplementation slightly increased triacylglycerol concentrations in healthy humans. Previous studies of phosphatidylcholine and blood lipids showed no clear effect. Thus the effect of phosphatidylcholine supplementation on blood lipids remains inconclusive, but is probably not large. Folic acid supplementation does not seem to affect blood lipids and therefore remains the preferred treatment for lowering of blood homocysteine concentrations.
Topics: Adult; Aged; Betaine; Cardiovascular Diseases; Female; Folic Acid; Homocysteine; Humans; Lipids; Lipotropic Agents; Male; Middle Aged; Phosphatidylcholines; Placebos; Risk Factors
PubMed: 15916468
DOI: 10.1371/journal.pmed.0020135 -
The Journal of Biological Chemistry Oct 2019Polyunsaturated fatty acids (PUFAs) such as α-linolenic acid (ALA, 18:3Δ ) have high nutritional and industrial values. In oilseed crops, PUFAs are synthesized on...
Polyunsaturated fatty acids (PUFAs) such as α-linolenic acid (ALA, 18:3Δ ) have high nutritional and industrial values. In oilseed crops, PUFAs are synthesized on phosphatidylcholine (PC) and accumulated in triacylglycerol (TAG). Therefore, exploring the mechanisms that route PC-derived PUFA to TAG is essential for understanding and improving PUFA production. The seed oil of flax () is enriched in ALA, and this plant has many lipid biosynthetic enzymes that prefer ALA-containing substrates. In this study, using membrane yeast two-hybrid and bimolecular fluorescence complementation assays, we probed recombinant flax transferase enzymes, previously shown to contribute to PUFA enrichment of TAG, for physical interactions with each other under conditions. We found that diacylglycerol acyltransferases, which catalyze the final reaction in acyl-CoA-dependent TAG biosynthesis, interact with the acyl-editing enzymes phosphatidylcholine: diacylglycerol cholinephosphotransferase, and lysophosphatidylcholine acyltransferase. Physical interactions among the acyl-editing enzymes were also identified. These findings reveal the presence of an assembly of interacting transferases that may facilitate the channeling of PUFA from PC to TAG in flax and possibly also in other oleaginous plants that produce seeds enriched in PC-modified fatty acids.
Topics: Diacylglycerol O-Acyltransferase; Fatty Acids, Unsaturated; Flax; Phosphatidylcholines; Protein Binding; Triglycerides; alpha-Linolenic Acid
PubMed: 31481466
DOI: 10.1074/jbc.AC119.010601 -
Journal of Lipid Research Oct 2018Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells,... (Comparative Study)
Comparative Study
Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [UC]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.
Topics: Animals; Biological Products; Lung; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Phosphatidylcholines; Phospholipids; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactants
PubMed: 30108154
DOI: 10.1194/jlr.M085431 -
The Journal of Physical Chemistry... May 2022Lipid bilayers play an important role in the pathological assembly of amyloidogenic proteins and peptides. This assembly yields oligomers and fibrils, which are highly...
Lipid bilayers play an important role in the pathological assembly of amyloidogenic proteins and peptides. This assembly yields oligomers and fibrils, which are highly toxic protein aggregates. In this study, we investigated the role of saturation in fatty acids of two phospholipids that are present in cell membranes. We found that unsaturated cardiolipin (CL) drastically shortened the lag phase of insulin aggregation. Furthermore, structurally and morphologically different aggregates were formed in the presence of unsaturated CL vs saturated CL. These aggregates exerted drastically different cell toxicity. Both saturated and unsaturated phosphatidylcholine (PC) were able to inhibit insulin aggregation equally efficiently. Similar to CL, structurally different aggregates were formed in the presence of saturated and unsaturated PC. These aggregates exerted different cell toxicities. These results show that unsaturated phospholipids catalyze the formation of more toxic amyloid aggregates comparing to those formed in the presence of saturated lipids.
Topics: Fatty Acids; Insulin; Lipid Bilayers; Phosphatidylcholines; Phospholipids
PubMed: 35580189
DOI: 10.1021/acs.jpclett.2c00559 -
Journal of Lipid Research Mar 1972The effect of transport of micelle-forming and non-micelle-forming conjugated bile salts on phosphatidylcholine synthesis and transport into bile was studied in the ex...
The effect of transport of micelle-forming and non-micelle-forming conjugated bile salts on phosphatidylcholine synthesis and transport into bile was studied in the ex vivo perfused rat liver. Single additions of sodium taurocholate, a good micelle-forming conjugated bile salt, caused an increase in bile flow associated with increased phosphatidylcholine and taurocholate concentration. The specific activity of phosphatidylcholine with respect to incorporated [1,2-(14)C]choline and [(3)H]methyl of l-[Me-(3)H]methionine was not significantly altered by the increased transport of phosphatidylcholine. The data suggested that bile phosphatidylcholine is synthesized to a great extent, although not exclusively, by phosphorylcholine glyceride transferase. Single additions of the glycine conjugate of dehydrocholate, a poor micelle-forming bile salt, caused an increase in bile flow comparable to that seen with sodium taurocholate administration. However, the concentrations of phosphatidylcholine in bile decreased. Thin-layer and gas-liquid chromatographic analyses of bile secreted before and after glycodehydrocholate administration revealed no significant increase in bile salt secretion other than the administered glycodehydrocholate. Investigations utilizing radiochemically pure [(14)C]glycine dehydrocholate revealed that increased bile flow after [(14)C]-glycine dehydrocholate administration occurs concomitantly with the secretion of 75-95% of the administered [(14)C]glycine dehydrocholate as a single peak into bile. Thus the increased bile flow without increased phosphatidylcholine concentration noted after glycodehydrocholate administration is due to transport of an intact, nonmetabolized, conjugated bile salt with poor micelle-forming properties. The data indicate that the formation of a bile salt-phosphatidylcholine micelle is responsible for phosphatidylcholine transport into bile.
Topics: Animals; Bile; Bile Acids and Salts; Biological Transport; Carbon Isotopes; Choline; Chromatography, Gas; Chromatography, Thin Layer; Colloids; Glycine; In Vitro Techniques; Liver; Macromolecular Substances; Methionine; Perfusion; Phosphatidylcholines; Phosphoric Acids; Rats; Tritium
PubMed: 5016305
DOI: No ID Found -
Inflammopharmacology Jun 2023Oxidised phospholipids such as oxidised palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) are increasingly recognised as danger-associated molecular patterns (DAMPs)...
Oxidised phospholipids such as oxidised palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) are increasingly recognised as danger-associated molecular patterns (DAMPs) inducing cyto- and chemokines. The pathological impact of oxidised phosphatidylcholine in vivo has been demonstrated in several animal models, as well as in human association studies. In this work, we have tested a number of small molecules with known or potential anti-inflammatory properties for their ability to inhibit secretion of interleukin-8 by OxPAPC-treated endothelial cells. Six compounds capable of inhibiting the induction of IL-8 were selected. Analysis of gene expression has shown that all these substances reduced the OxPAPC-induced elevation of IL-8 mRNA but potentiated induction of heat-shock proteins (HSPs). We further found that drug-like HSP inducers also prevented the induction of IL-8 by OxPAPC. Similar inhibitory action was demonstrated by two chemical chaperones, which stabilise proteins through physicochemical mechanisms thus mimicking effects of HSPs. Our data suggest that proteostatic stress plays an important mechanistic role in the pro-inflammatory effects of OxPAPC and that stabilisation of proteome by overexpression of HSPs or by chemical chaperones can reduce the pro-inflammatory effects of OxPLs.
Topics: Animals; Humans; Phospholipids; Interleukin-8; Up-Regulation; Endothelial Cells; Heat-Shock Proteins; Phosphatidylcholines
PubMed: 36692663
DOI: 10.1007/s10787-022-01124-6 -
The EMBO Journal Aug 2006CD1 proteins present lipid antigens to T cells. The antigens are acquired in the endosomal compartments. This raises the question of how the large hydrophobic CD1...
CD1 proteins present lipid antigens to T cells. The antigens are acquired in the endosomal compartments. This raises the question of how the large hydrophobic CD1 pockets are preserved between the moment of biosynthesis in the endoplasmic reticulum and arrival to the endosomes. To address this issue, the natural ligands associated with a soluble form of human CD1b have been investigated. Using isoelectric focusing, native mass spectrometry and resolving the crystal structure at 1.8 A resolution, we found that human CD1b is simultaneously associated with endogenous phosphatidylcholine (PC) and a 41-44 carbon atoms-long spacer molecule. The two lipids appear to work in concert to stabilize the CD1b groove, their combined size slightly exceeding the maximal groove capacity. We propose that the spacer serves to prevent binding of ligands with long lipid tails, whereas short-chain lipids might still displace the PC, which is exposed at the groove entrance. The data presented herein explain how the CD1b groove is preserved, and provide a rationale for the in vivo antigen-binding properties of CD1b.
Topics: Antigens, CD1; Binding Sites; Crystallography, X-Ray; Humans; Hydrophobic and Hydrophilic Interactions; Isoelectric Focusing; Ligands; Mass Spectrometry; Models, Molecular; Phosphatidylcholines; Protein Binding; Protein Conformation; Protein Folding
PubMed: 16874306
DOI: 10.1038/sj.emboj.7601244 -
Xenobiotica; the Fate of Foreign... Mar 20151.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of...
1.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2.UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3.About 50 μM of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased.
Topics: Biocatalysis; Catalytic Domain; Glucuronides; Glucuronosyltransferase; Humans; Kinetics; Lysophosphatidylcholines; Molecular Docking Simulation; Phosphatidylcholines; Protein Isoforms; Recombinant Proteins
PubMed: 25259654
DOI: 10.3109/00498254.2014.966174