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Biophysical Journal Mar 2023Bilayer membranes composed of cholesterol and phospholipids exhibit diverse forms of nonideal mixing. In particular, many previous studies document macroscopic...
Bilayer membranes composed of cholesterol and phospholipids exhibit diverse forms of nonideal mixing. In particular, many previous studies document macroscopic liquid-liquid phase separation as well as nanometer-scale heterogeneity in membranes of phosphatidylcholine (PC) lipids and cholesterol. Here, we present experimental measurements of cholesterol chemical potential (μ) in binary membranes containing dioleoyl PC (DOPC), 1-palmitoyl-2-oleoyl PC (POPC), or dipalmitoyl PC (DPPC), and in ternary membranes of DOPC and DPPC, referenced to crystalline cholesterol. μ is the thermodynamic quantity that dictates the availability of cholesterol to bind other factors, and notably must be equal between coexisting phases of a phase separated mixture. It is simply related to concentration under conditions of ideal mixing, but is far from ideal for the majority of lipid mixtures investigated here. Measurements of μ can vary with phospholipid composition by 1.5 kT at constant cholesterol mole fraction implying a more than fivefold change in its availability for binding receptors and other reactions. Experimental measurements are fit to thermodynamic models including cholesterol-DPPC complexes or pairwise interactions between lipid species to provide intuition about the magnitude of interactions. These findings reinforce that μ depends on membrane composition overall, suggesting avenues for cells to alter the availability of cholesterol without varying cholesterol concentration.
Topics: Phosphatidylcholines; Cholesterol; Thermodynamics; Lipid Bilayers
PubMed: 36785512
DOI: 10.1016/j.bpj.2023.02.009 -
Chemistry and Physics of Lipids May 2023Sphingomyelin (SM) and cholesterol complex to form functional liquid-ordered (L) domains. It has been suggested that the detergent resistance of these domains plays a...
Sphingomyelin (SM) and cholesterol complex to form functional liquid-ordered (L) domains. It has been suggested that the detergent resistance of these domains plays a key role during gastrointestinal digestion of the milk fat globule membrane (MFGM), which is rich in both SM and cholesterol. Small-angle X-ray scattering was employed to determine the structural alterations that occur when milk sphingomyelin (MSM)/cholesterol, egg sphingomyelin (ESM)/cholesterol, soy phosphatidylcholine (SPC)/cholesterol, and milk fat globule membrane (MFGM) phospholipid/cholesterol model bilayer systems were incubated with bovine bile under physiological conditions. The persistence of diffraction peaks was indicative of multilamellar vesicles of MSM with cholesterol concentrations > 20 % mol, and also for ESM with or without cholesterol. The complexation of ESM with cholesterol is therefore capable of inhibiting the resulting vesicles from disruption by bile at lower cholesterol concentrations than MSM/cholesterol. After subtraction of background scattering by large aggregates in the bile, a Guinier fitting was used to determine changes in the radii of gyration (Rs) over time for the biliary mixed micelles after mixing the vesicle dispersions with bile. Swelling of the micelles by phospholipid solubilization from vesicles was a function of cholesterol concentration, with less swelling of the micelles occurring as the cholesterol concentration was increased. With 40% mol cholesterol, the Rs of the bile micelles mixed with MSM/cholesterol, ESM/cholesterol, and MFGM phospholipid/cholesterol were equal to the control (PIPES buffer + bovine bile), indicating negligible swelling of the biliary mixed micelles.
Topics: Animals; Cattle; Phospholipids; Bile; Micelles; Sphingomyelins; Bile Acids and Salts; Phosphatidylcholines; Cholesterol; Lecithins
PubMed: 36813145
DOI: 10.1016/j.chemphyslip.2023.105289 -
Bioscience, Biotechnology, and... Apr 2021Phosphatidylcholine (PC) is an essential component of the plasma membrane. Its profile varies with species and tissues. However, the PC profiles in meat have not been...
Phosphatidylcholine (PC) is an essential component of the plasma membrane. Its profile varies with species and tissues. However, the PC profiles in meat have not been explored in depth. This study aimed to investigate the differences in PC profiles between various meat animal species and meat cut sites, along with the identification of characteristic PC molecules. The results demonstrated that the PC profiles of chicken meat differed from those of other species. Significant differences were also observed between the PC profiles of pork meat and the meat obtained from other species. The amount of PCs containing ether bonds was high in pork meat. PCs containing an odd number of carbon atoms were characteristic of beef and lamb meats. Furthermore, PC profiles differed based on the muscle location in chicken and pork. These results suggest that the PC profiles of skeletal muscles are indicators of animal species and muscle location.
Topics: Animals; Cattle; Chickens; Chromatography, Liquid; Food Analysis; Lipidomics; Meat; Muscle, Skeletal; Organ Specificity; Phosphatidylcholines; Principal Component Analysis; Sheep; Species Specificity; Spectrometry, Mass, Electrospray Ionization; Swine
PubMed: 33686423
DOI: 10.1093/bbb/zbab010 -
Biomeditsinskaia Khimiia 2015A new generation of plant phosphatidylcholine (PC)-based pharmacological agents has been developed under academician A.I. Archakov leadership at the Institute of... (Review)
Review
A new generation of plant phosphatidylcholine (PC)-based pharmacological agents has been developed under academician A.I. Archakov leadership at the Institute of Biomedical Chemistry (IBMC). For their production a unique technology allowing to obtain dry lyophilized phospholipid nanoparticles of 30 nm was elaborated. The successful practical application of PC nanoparticles as a drug agent may be illustrated by Phosphogliv (oral and injection formulations). Being developed at IBMC for the treatment of liver diseases, including viral hepatitis, Phosphogliv (currently marketed by the "Pharmstandard" company) is approved for clinical application in 2000, and is widely used in medical practice. Based on the developed and scaled in IBMC technology of prerparation of ultra small size phospholipid nanoparticles without the use of detergents/surfactants and stabilizers another drug preparation, Phospholipovit, exhibiting pronounced hypolipidemic properties has been obtained. Recently completed preclinical studies have shown that PC nanoparticles of 20-30 nm activate reverse cholesterol transport (RCT) and in this context it is more active than well known foreign preparation Essentiale. Phospholipovit is now at the stage of clinical trials (phase 1 completed). PC was also used as a basis for the development of a transport nanosystem with a particles size of 20-25 nm in diameter and incorporation of various drug substances from various therapeutic groups. Using several drugs substances as an example, increased bioavailability and specific activity were demonstrated for the formulations equipped with such transport nanosystem. Formulations equipped with the transport nanosystems have been developed for such pharmacological agents as doxorubicin, rifampin, budesonide, chlorin E6, prednisone, and others.
Topics: Animals; Biological Availability; Cholesterol; Doxorubicin; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Design; Glycyrrhizic Acid; Humans; Nanoparticles; Nanostructures; Particle Size; Phosphatidylcholines; Phospholipids; Rifampin
PubMed: 25978388
DOI: 10.18097/PBMC20156102219 -
Distributing aminophospholipids asymmetrically across leaflets causes anomalous membrane stiffening.Biophysical Journal Jun 2023We studied the mechanical leaflet coupling of prototypic mammalian plasma membranes using neutron spin-echo spectroscopy. In particular, we examined a series of...
We studied the mechanical leaflet coupling of prototypic mammalian plasma membranes using neutron spin-echo spectroscopy. In particular, we examined a series of asymmetric phospholipid vesicles with phosphatidylcholine and sphingomyelin enriched in the outer leaflet and inner leaflets composed of phosphatidylethanolamine/phosphatidylserine mixtures. The bending rigidities of most asymmetric membranes were anomalously high, exceeding even those of symmetric membranes formed from their cognate leaflets. Only asymmetric vesicles with outer leaflets enriched in sphingolipid displayed bending rigidities in conformity with these symmetric controls. We performed complementary small-angle neutron and x-ray experiments on the same vesicles to examine possible links to structural coupling mechanisms, which would show up in corresponding changes in membrane thickness. In addition, we estimated differential stress between leaflets originating either from a mismatch of their lateral areas or spontaneous curvatures. However, no correlation with asymmetry-induced membrane stiffening was observed. To reconcile our findings, we speculate that an asymmetric distribution of charged or H-bond forming lipids may induce an intraleaflet coupling, which increases the weight of hard undulatory modes of membrane fluctuations and hence the overall membrane stiffness.
Topics: Animals; Cell Membrane; Phospholipids; Membranes; Phosphatidylcholines; Sphingomyelins; Lipid Bilayers; Mammals
PubMed: 37120716
DOI: 10.1016/j.bpj.2023.04.025 -
The Analyst Oct 2022Characterization of glycerophospholipid isomers is of significant importance as they play different roles in physiological and pathological processes. In this work, we...
Characterization of glycerophospholipid isomers is of significant importance as they play different roles in physiological and pathological processes. In this work, we present a novel and bifunctional derivatization method utilizing Mn(II)-catalyzed epoxidation to simultaneously identify carbon-carbon double bond (CC bond)- and stereonumbering ()-positional isomers of phosphatidylcholine. Mn(II) coordinates with picolinic acid and catalyzes epoxidation of unsaturated lipids by peracetic acid. Collision-induced dissociation (CID) of the epoxides generates diagnostic ions that can be used to locate CC bond positions. Meanwhile, CID of Mn(II) ion-lipid complexes produces characteristic ions for determination of positions. This bifunctional derivatization takes place in seconds, and the diagnostic ions produced in CID are clear and easy to interpret. Moreover, relative quantification of CC bond-and -positional isomers was achieved. The capability of this method in identifying lipids at multiple isomer levels was shown using lipid standards and lipid extracts from complex biological samples.
Topics: Glycerophospholipids; Peracetic Acid; Phosphatidylcholines; Ions; Epoxy Compounds; Carbon; Catalysis
PubMed: 36128870
DOI: 10.1039/d2an01174c -
Frontiers in Immunology 2022Chronic urticaria (CU) is a chronic inflammatory skin disease mainly mediated by mast cells. Lipids exert essential functions in biological processes; however, the role...
Chronic urticaria (CU) is a chronic inflammatory skin disease mainly mediated by mast cells. Lipids exert essential functions in biological processes; however, the role of lipids in CU remains unclear. Nontargeted lipidomics was performed to investigate the differential lipid profiles between CU patients and healthy control (HC) subjects. Functional validation studies were performed and including β-hexosaminidase release examination from mast cells and passive cutaneous anaphylaxis (PCA) mouse model. We detected dramatically altered glycerophospholipids in CU patients compared with HCs. Phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) were increased, while phosphatidylcholine (PC) was reduced in CU patients. The reduction in PC was related to a high weekly urticaria activity score (UAS7), while PS was positively associated with the dermatology life quality index (DLQI). We also identified the differential lipid profiles between chronic spontaneous urticaria (CSU), symptomatic dermographism (SD), and CSU coexist with SD. CU patients were classified into two subtypes (subtype 1 and subtype 2) based on consensus clustering of lipid profiling. Compared with patients in subtype 2, patients in subtype 1 had elevated levels of PC (18:0e/18:2) and PE (38:2), and lower urticaria control test (UCT) scores indicated worse clinical efficiency of secondary generation H1 antihistamines treatment. Importantly, we found that supplementation with PC could attenuate IgE-induced immune responses in mast cells. In general, We described the landscape of plasma lipid alterations in CU patients and provided novel insights into the role of PC in mast cells.
Topics: Animals; Chronic Disease; Chronic Urticaria; Humans; Lipidomics; Mice; Phosphatidylcholines; Urticaria
PubMed: 35967440
DOI: 10.3389/fimmu.2022.933312 -
Current Opinion in Lipidology Jun 2022The turnover of fatty acids (FAs) at the sn-2 position of phospholipids is mediated by the reciprocal actions of phospholipases A2 and lyso-PL acyltransferases (LPLAT).... (Review)
Review
PURPOSE OF REVIEW
The turnover of fatty acids (FAs) at the sn-2 position of phospholipids is mediated by the reciprocal actions of phospholipases A2 and lyso-PL acyltransferases (LPLAT). LPCAT3, a major LPLAT isoform, exhibits a strong specificity for polyunsaturated FAs s (PUFAs). Although the enzyme was originally studied in the context of cardiometabolism, recent investigations have shed light on the role of LPCAT3 in other tissues such as skeletal muscle and in unexpected biological processes such as cell death and oncogenesis.
RECENT FINDINGS
The three-dimensional structure of LPCAT3 has been elucidated allowing further understanding of the mechanism of the acylation reaction as well as the substrate specificity of the enzyme. In skeletal muscle, LPCAT3-mediated phospholipid remodeling modulates membrane domain clustering and insulin signalingLPCAT3 plays an important role in the process of ferroptosis by modulating the PUFA content of phospholipids and possibly of plasmalogens.In tumor-associated macrophages, LPCAT3 can prevent ER stress induced by the tumor microenvironment and may equally modulate antitumor immunity.
SUMMARY
LPCAT3 is an attractive therapeutic target in the cardiometabolic disorders. Nevertheless, the involvement of LPCAT3 in processes such as cell death and oncogenesis demands caution with respect to the potential deleterious effects of enzyme modulation.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Acyltransferases; Carcinogenesis; Humans; Phosphatidylcholine-Sterol O-Acyltransferase; Phosphatidylcholines; Phospholipids; Tumor Microenvironment
PubMed: 35165232
DOI: 10.1097/MOL.0000000000000820 -
Lipids Feb 2018Phospholipids have been shown to modulate intestinal cholesterol absorption in cells and animals, a process that is regulated by several transporter proteins. Of these...
Phospholipids have been shown to modulate intestinal cholesterol absorption in cells and animals, a process that is regulated by several transporter proteins. Of these proteins, Niemann-Pick C1-Like 1 (NPC1L1) is a major contributor to this process. The mechanism by which phospholipids modulate cholesterol absorption remains unknown. Here, we evaluate the effects of egg-yolk phospholipids on cholesterol absorption and transport in human colon carcinoma cell line (Caco-2 cells) and on the expression of NPC1L1 and others proteins associated with cholesterol absorption (ABCG5, ABCG8, ABCA1, ACAT2, MTP, CAV-1, ANX-2). The roles of SREBP-1 and SREBP-2 in this process were also investigated. The results show that egg-yolk sphingomyelin (CerPCho) and phosphatidylcholine (PtdCho) inhibit cholesterol transport in the Caco-2 monolayer in a dose-dependent manner. These might be due to the decrease of the cholesterol solubility in micelles as well as to the increases in the micellar sizes and the bile acid-binding capacity. Furthermore, the treatments with egg-yolk CerPCho or PtdCho at 1.2 mmol/L reduced the expression levels of NPC1L1 protein to 21 or 22%, respectively, and its mRNA to 9 or 31% of that in the control group (p < 0.05). Moreover, there was a general inhibitory effect of egg-yolk PtdCho and CerPCho on the mRNA levels of SREBP-1, and SREBP-2. These results suggest that the inhibitory effect of egg-yolk CerPCho and PtdCho on cholesterol transport might be due to their interference with the physicochemical properties of micelles and their regulations on the expression of the NPC1L1 gene.
Topics: Absorption, Physiological; Caco-2 Cells; Cholesterol; Egg Yolk; Humans; Phosphatidylcholines; Sphingomyelins
PubMed: 29569242
DOI: 10.1002/lipd.12018 -
The Journal of Physical Chemistry. B Aug 2014As plasma membranes of animal cells are known to be asymmetric, the transmembrane lipid asymmetry, being essential for many membranes' properties and functions, should...
As plasma membranes of animal cells are known to be asymmetric, the transmembrane lipid asymmetry, being essential for many membranes' properties and functions, should be properly accounted for in model membrane systems. In this paper, we employ atomic-scale molecular dynamics simulations to explore electroporation phenomena in asymmetric model membranes comprised of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipid monolayers that mimic the outer and inner leaflets of plasma membranes, respectively. Our findings clearly demonstrate that the molecular mechanism of electroporation in asymmetric phospholipid membranes differs considerably from the picture observed for their single-component symmetric counterparts: The initial stages of electric-field-induced formation of a water-filled pore turn out to be asymmetric and occur mainly on the PC side of the PC/PE membrane. In particular, water molecules penetrate in the membrane interior mostly from the PC side, and the reorientation of lipid head groups, being crucial for stabilizing the hydrophilic pore, also takes place in the PC leaflet. In contrast, the PE lipid head groups do not enter the central region of the membrane until the water pore becomes rather large and partly stabilized by PC head groups. Such behavior implies that the PE leaflet is considerably more robust against an electric field most likely due to interlipid hydrogen bonding. We also show that an electric field induces asymmetric changes in the lateral pressure profile of PC/PE membranes, decreasing the cohesion between lipid molecules predominantly in the PC membrane leaflet. Overall, our simulations provide compelling evidence that the transmembrane lipid asymmetry can be essential for understanding electroporation phenomena in living cells.
Topics: Animals; Electricity; Electroporation; Molecular Dynamics Simulation; Phosphatidylcholines; Phosphatidylethanolamines; Unilamellar Liposomes
PubMed: 24986456
DOI: 10.1021/jp5028355