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Nature Communications Nov 2021As the major component of cell membranes, phosphatidylcholine (PC) is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation...
As the major component of cell membranes, phosphatidylcholine (PC) is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation remodeling via Lands' cycle. The re-acylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT) and among the four LPCAT members in human, the LPCAT3 preferentially introduces polyunsaturated acyl onto the sn-2 position of lysophosphatidylcholine, thereby modulating the membrane fluidity and membrane protein functions therein. Combining the x-ray crystallography and the cryo-electron microscopy, we determined the structures of LPCAT3 in apo-, acyl donor-bound, and acyl receptor-bound states. A reaction chamber was revealed in the LPCAT3 structure where the lysophosphatidylcholine and arachidonoyl-CoA were positioned in two tunnels connected near to the catalytic center. A side pocket was found expanding the tunnel for the arachidonoyl CoA and holding the main body of arachidonoyl. The structural and functional analysis provides the basis for the re-acylation of lysophosphatidylcholine and the substrate preference during the reactions.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Acyl Coenzyme A; Acylation; Animals; Catalytic Domain; Chickens; Cryoelectron Microscopy; Crystallography, X-Ray; Lysophosphatidylcholines; Models, Molecular; Phospholipids; Protein Multimerization; Structure-Activity Relationship; Substrate Specificity
PubMed: 34824256
DOI: 10.1038/s41467-021-27244-1 -
Journal of Lipid Research Mar 2019EPA and DHA protect against multiple metabolic and neurologic disorders. Although DHA appears more effective for neuroinflammatory conditions, EPA is more beneficial for...
EPA and DHA protect against multiple metabolic and neurologic disorders. Although DHA appears more effective for neuroinflammatory conditions, EPA is more beneficial for depression. However, the brain contains negligible amounts of EPA, and dietary supplements fail to increase it appreciably. We tested the hypothesis that this failure is due to absorption of EPA as triacylglycerol, whereas the transporter at the blood-brain barrier requires EPA as lysophosphatidylcholine (LPC). We compared tissue uptake in normal mice gavaged with equal amounts (3.3 μmol/day) of either LPC-EPA or free EPA (surrogate for current supplements) for 15 days and also measured target gene expression. Compared with the no-EPA control, LPC-EPA increased brain EPA >100-fold (from 0.03 to 4 μmol/g); free EPA had little effect. Furthermore, LPC-EPA, but not free EPA, increased brain DHA 2-fold. Free EPA increased EPA in adipose tissue, and both supplements increased EPA and DHA in the liver and heart. Only LPC-EPA increased EPA and DHA in the retina, and expression of brain-derived neurotrophic factor, cyclic AMP response element binding protein, and 5-hydroxy tryptamine (serotonin) receptor 1A in the brain. These novel results show that brain EPA can be increased through diet. Because LPC-EPA increased both EPA and DHA in the brain, it may help in the treatment of depression as well as neuroinflammatory diseases, such as Alzheimer's disease.
Topics: Animals; Brain; Depression; Diet; Docosahexaenoic Acids; Eicosapentaenoic Acid; Gene Expression Regulation; Lysophosphatidylcholines; Male; Mice; Mice, Inbred C57BL; Retina
PubMed: 30530735
DOI: 10.1194/jlr.M090464 -
Journal of Colloid and Interface Science Jan 2023The surface dilatational and shear moduli of surfactant and protein interfacial layers can be derived from surface pressures measured with a Wilhelmy plate parallel,...
HYPOTHESIS
The surface dilatational and shear moduli of surfactant and protein interfacial layers can be derived from surface pressures measured with a Wilhelmy plate parallel, ΔΠ and perpendicular ΔΠ to the barriers in a Langmuir trough.
EXPERIMENTAL
Applying area oscillations, A+ ΔAe, in a rectangular Langmuir trough induces changes in surface pressure, ΔΠ and ΔΠ for monolayers of soluble palmitoyl-lysophosphatidylcholine (LysoPC), insoluble dipalmitoylphosphatidylcholine (DPPC), and the protein β-lactoglobulin to evaluate E+G=AΔΠΔA and E-G=AΔΠΔA. G was independently measured with a double-wall ring apparatus (DWR) and E by area oscillations of hemispherical bubbles in a capillary pressure microtensiometer (CPM) and the results were compared to the trough measurements.
FINDINGS
For LysoPC and DPPC, AΔΠΔA≅AΔΠΔA meaning E≫G and E≅AΔΠΔA≅AΔΠΔA. Trough values for E were quantitatively similar to CPM when corrected for interfacial curvature. DWR showed G was 4 orders of magnitude smaller than E for both LysoPC and DPPC. For β-lactoglobulin films, AΔΠΔA>AΔΠΔA and E and G were in qualitative agreement with independent CPM and DWR measurements. For β-lactoglobulin, both E and G varied with film age and history on the trough, suggesting the evolution of the protein structure.
Topics: Lysophosphatidylcholines; 1,2-Dipalmitoylphosphatidylcholine; Surface Properties; Rheology; Lactoglobulins; Surface-Active Agents; Water
PubMed: 36063630
DOI: 10.1016/j.jcis.2022.08.051 -
Clinical and Translational Medicine Jan 2023Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the...
Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long-chain acyl-coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5-downregulated epithelia. ACSL5 over-expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5/phosphoinositide 3-kinase/extracellular signal-regulated kinase-regulated triacylglycerol-lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine.
Topics: Humans; Cell Proliferation; Fatty Acids; Lung Neoplasms; Lysophosphatidylcholines; Phosphatidylinositol 3-Kinases; Coenzyme A Ligases
PubMed: 36639836
DOI: 10.1002/ctm2.1180 -
Scientific Reports May 2022Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck...
Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs' production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.
Topics: Animals; Brain; Chromatography, Liquid; Inflammation; Ivermectin; Lysophosphatidylcholines; Lysophospholipids; Memory Disorders; Mice; Microglia; Necrosis; Receptors, Purinergic P2X4; Tandem Mass Spectrometry
PubMed: 35610277
DOI: 10.1038/s41598-022-12293-3 -
Cell Dec 2017Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in...
Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.
Topics: Animals; Cell Differentiation; Humans; Lysophosphatidylcholines; Malaria; Parasites; Plasmodium falciparum; Sex Differentiation
PubMed: 29245007
DOI: 10.1016/j.cell.2017.11.044 -
Journal of Cellular and Molecular... Jul 2020This study aims to explore lipidic mechanism towards low-density lipoprotein receptor (LDLR)-mediated platinum chemotherapy resistance. By using the lipid profiling...
This study aims to explore lipidic mechanism towards low-density lipoprotein receptor (LDLR)-mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down-regulated ether-linked phosphatidylethanolamine (PE-O, lysosomes or peroxisomes) and up-regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR-related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum-DNA adducts and reduced the LD platinum amount. By using a manufactured LPC-liposome-cisplatin (LLC) drug, the number of platinum-DNA adducts increased significantly in LLC-treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin-insensitive human carcinoma cell training and testing sets. Thus, LDLR-platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method.
Topics: Animals; Cell Line, Tumor; Cisplatin; Female; Humans; Lipid Droplets; Lipidomics; Liposomes; Lysophosphatidylcholines; Mice, Nude; Models, Biological; Receptors, LDL
PubMed: 32543783
DOI: 10.1111/jcmm.15218 -
The FEBS Journal Nov 2013Glycerophosphocholines are the major building blocks of biological membranes. They are also precursors of low-molecular-weight second messengers with mass to charge... (Review)
Review
Glycerophosphocholines are the major building blocks of biological membranes. They are also precursors of low-molecular-weight second messengers with mass to charge ratios of 450-600. These messengers include lysophosphatidylcholines (LPCs) and lyso-platelet activating factors (PAFs) that may be further processed into PAFs. Often considered as a single species, LPCs, PAFs and lyso-PAFs are, in fact, families of glycerophosphocholine-derived lipids distinguished by the linkage of their sn-1 carbon chains to the phosphoglyceride backbone (ester or ether), their sn-1 carbon chain length and degree of unsaturation, and the identity of their sn-2 constituents (a hydroxyl or acetyl group). Each LPC and PAF species exhibits a different affinity for its cognate G-protein-coupled receptors, and each species elicits receptor-independent actions that play critical signalling roles. Targeted mass spectrometry-based lipidomic approaches are enabling the molecular identification and quantification of these low-abundance second messengers. Variations between datasets map the temporal landscape of second messengers available for signalling, and provide snapshots of the state of structural membrane compositional remodelling at the time of extraction. Here, we review a number of advances in lipidomic methodologies used to identify LPCs, lyso-PAFs and PAFs, and highlight how these targeted approaches are providing valuable insight into the roles played by the cellular lipidome in cell function and disease susceptibility.
Topics: Humans; Lipid Metabolism; Lysophosphatidylcholines; Mass Spectrometry; Membrane Lipids; Metabolome; Metabolomics; Platelet Activating Factor; Second Messenger Systems
PubMed: 23826908
DOI: 10.1111/febs.12423 -
The Journal of Biological Chemistry Mar 2022Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases,...
Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases, such as acute respiratory distress syndromes, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Pulmonary surfactant is primarily composed of phosphatidylcholine (PC) in complex with specialized surfactant proteins and secreted by alveolar type 2 (AT2) cells. Surfactant homeostasis on the alveolar surface is balanced by the rates of synthesis and secretion with reuptake and recycling by AT2 cells, with some degradation by pulmonary macrophages and loss up the bronchial tree. However, whether phospholipid (PL) transporters exist in AT2 cells to mediate reuptake of surfactant PL remains to be identified. Here, we demonstrate that major facilitator superfamily domain containing 2a (Mfsd2a), a sodium-dependent lysophosphatidylcholine (LPC) transporter, is expressed at the apical surface of AT2 cells. A mouse model with inducible AT2 cell-specific deficiency of Mfsd2a exhibited AT2 cell hypertrophy with reduced total surfactant PL levels because of reductions in the most abundant surfactants, PC containing dipalmitic acid, and PC species containing the omega-3 fatty acid docosahexaenoic acid. These changes in surfactant levels and composition were mirrored by similar changes in the AT2 cell lipidome. Mechanistically, direct tracheal instillation of fluorescent LPC and PC probes indicated that Mfsd2a mediates the uptake of LPC generated by pulmonary phospholipase activity in the alveolar space. These studies reveal that Mfsd2a-mediated LPC uptake is quantitatively important in maintaining surfactant homeostasis and identify this lipid transporter as a physiological component of surfactant recycling.
Topics: Animals; Docosahexaenoic Acids; Homeostasis; Lung; Lysophosphatidylcholines; Membrane Transport Proteins; Mice; Phosphatidylcholines; Phospholipids; Pulmonary Surfactants; Symporters
PubMed: 35150739
DOI: 10.1016/j.jbc.2022.101709 -
World Journal of Gastroenterology Sep 2013To analyze phospholipid profiles in intrahepatic bile from patients with primary sclerosing cholangitis (PSC) and secondary sclerosing cholangitis (SSC). (Comparative Study)
Comparative Study
AIM
To analyze phospholipid profiles in intrahepatic bile from patients with primary sclerosing cholangitis (PSC) and secondary sclerosing cholangitis (SSC).
METHODS
Intrahepatic bile specimens collected via endoscopic retrograde cholangiography from 41 patients were analyzed. Fourteen of these patients were diagnosed with PSC, 10 with SSC, 11 with choledocholithiasis or no identifiable biliary disease, and 6 with cholangiocellular carcinoma (CCC). Bile acid, cholesterol, protein, and bilirubin contents as well as pancreas lipase activity in bile were determined by biochemical methods. Phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species were quantified using nano-electrospray ionization tandem mass spectrometry.
RESULTS
Bile from all the examined patient groups showed a remarkably similar PC and LPC species composition, with only minor statistical differences. Total biliary PC concentrations were highest in controls (8030 ± 1843 μmol/L) and lowest in patients with CCC (1969 ± 981 μmol/L) (P = 0.005, controls vs SSC and CCC, respectively, P < 0.05). LPC contents in bile were overall low (4.2% ± 1.8%). Biliary LPC/PC ratios and ratios of biliary PC to bilirubin, PC to cholesterol, PC to protein, and PC to bile acids showed no intergroup differences.
CONCLUSION
PC and LPC profiles being similar in patients with or without sclerosing cholangitis, these phospholipids are likely not of major pathogenetic importance in this disease group.
Topics: Adult; Aged; Aged, 80 and over; Bile; Case-Control Studies; Cholangitis, Sclerosing; Female; Humans; Lysophosphatidylcholines; Male; Middle Aged; Phosphatidylcholines; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Young Adult
PubMed: 24023488
DOI: 10.3748/wjg.v19.i33.5454