Saturated Phosphatidylcholine Research Articles

Lysophospholipid acyltransferase-mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation.

Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi-omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up-regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1-mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia-related diseases.

Light intensity influences the glycerolipid remodeling of Gracilariopsis lemaneiformis in response to short-term high temperature stress

Temperature and light are two pivotal environmental factors for the growth of marine photosynthetic organisms. While the responses of Gracilariopsis lemaneiformis to individual high temperature or light stress have been explored, our understanding of its combined stress responses remains limited. This study aimed to investigate the combined effects of short-term high temperature (33 °C, 8 h) and different light intensities, that is, low light (LL, 50 μmol photon m−2 s−1), medium light (ML, 150 μmol photon m−2 s−1), and high light (HL, 300 μmol photon m−2 s−1), on the physiological responses and lipid remodeling of G. lemaneiformis. Results demonstrated that short-term exposure to either high temperature or high light stress led to a reduction in maximum (Fv/Fm), effective photochemical efficiency (Fv'/Fm') and maximum relative electron transfer rate (rETRmax), and the combination of these stresses exerted a more pronounced inhibitory effect on photosystem II efficiency. Short-term exposure to heat stress led to an increase in superoxide dismutase (SOD) activity, as well as a rise in glutathione (GSH) and ascorbate (Asc) contents under LL, while the activities of antioxidant enzymes (SOD, peroxidase, and ascorbate peroxidase) and levels of non-enzymatic antioxidants (GSH and Asc) were reduced under ML and HL. Additionally, short-term heat stress induced the accumulations of phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, sulfoquinovosyldiacylglycerol, and triacylglycerol (TAG) under LL, while heat-induced lipid accumulation decreased under ML and HL. Furthermore, heat stress increased the accumulation of saturated or unsaturated PC species under LL. Specifically, there was an increase in the levels of saturated or monounsaturated acyl chain–containing PC species, whereas the levels of polyunsaturated acyl chain-containing PC species declined under ML and HL. Correspondingly, a significant increase in TAG species with polyunsaturated acyl chains was observed, particularly under LL conditions, suggesting a potential lipid turnover between PC and TAG. These results showed that the lipid metabolic plasticity of G. lemaneiformis enabled it to rapidly adapt to fluctuating environmental conditions, and the light environment regulated its heat stress response.

Lipid composition and properties affect protein-mediated carotenoid uptake efficiency from membranes

Carotenoids are pigments of diverse functions ranging from coloration over light-harvesting to photoprotection. Yet, the number of carotenoid-binding proteins, which mobilize these pigments in physiological media, is limited, and the mechanisms of carotenoid mobilization are still not well understood. The same applies for the determinants of carotenoid uptake from membranes into carotenoproteins, especially regarding the dependence on the chemical properties of membrane lipids. Here, we investigate xanthophyll uptake capacity and kinetics of a paradigmatic carotenoid-binding protein, the homolog of the Orange Carotenoid Protein's C-terminal domain from Anabaena sp. PCC 7120 (AnaCTDH), using liposomes formed from defined lipid species and loaded with canthaxanthin (CAN) and echinenone (ECN), respectively. Phospholipids with different chain length and degree of saturation were investigated. The composition of carotenoid-loaded liposomes directly affected the incorporation yield and storage ratio of CAN and ECN as well as the rate of carotenoid uptake by AnaCTDH. Generally, saturated PC lipids were identified as unsuitable, and a high phase transition temperature of the lipids negatively affected the carotenoid incorporation and storage yield. For efficient carotenoid transfer, the velocity increases with increasing chain length or membrane thickness. An average transfer yield of 93 % and 43 % were obtained for the formation of AnaCTDH(CAN) and AnaCTDH(ECN) holoproteins, respectively. In summary, the most suitable lipids for the formation of AnaCTDH(CAN/ECN) holoproteins by carotenoid transfer from artificial liposomes are phosphatidylcholine (18:1) and phosphatidylglycerol (14:0). Thus, these two lipids provide the best conditions for further investigation of lipid-protein interaction and the carotenoid uptake process.

Arrangement of lipid vesicles and bicelle-like structures formed in the presence of Aβ(25–35) peptide

Our complementary experimental data and molecular dynamics (MD) simulations results reveal the structure of previously observed lipid bicelle-like structures (BLSs) formed in the presence of amyloid-beta peptide Aβ(25–35) below the main phase transition temperature (Tm) of saturated phosphatidylcholine lipids and small unilamellar vesicles (SUVs) above this temperature. First, we show by using solid-state 31P nuclear magnetic resonance (NMR) spectroscopy that our BLSs being in the lipid gel phase demonstrate magnetic alignment along the magnetic field of NMR spectrometer and undergo a transition to SUVs in the lipid fluid phase when heated through the Tm. Secondly, thanks to the BLS alignment we present their lipid structure. Lipids are found located not only in the flat bilayered part but also around its perimeter, which is corroborated by the results of coarse-grained (CG) MD simulations. Finally, peptides appear to mix randomly with lipids in SUVs while assuming predominantly unordered secondary structures revealed by circular dichroism (CD), Raman spectroscopy, and all-atom MD simulations. Importantly, the former is changing little when the system undergoes morphological transitions between BLSs and SUVs. Our structural results then offer a platform for studying and understanding mechanisms of morphological transformations caused by the disruptive effect of amyloid-beta peptides on the lipid bilayer.

Metabolite profiling of peripheral blood plasma in pigs in early postnatal life fed whole bovine, caprine or ovine milk.

Ruminants' milk is commonly used for supplying nutrients to infants when breast milk is unavailable or limited. Previous studies have highlighted the differences between ruminants' milk composition, digestion, absorption, and fermentation. However, whether consuming different ruminants' milk impact the appearance of the circulatory blood metabolites in the early postnatal life is not well understood. The analysis conducted here aimed to determine the effect of feeding exclusively whole milk from bovine, caprine or ovine species to pigs, approximately 7 days-old for 15 days, on circulatory blood plasma metabolites. Relative intensities of plasma metabolites were detected using a liquid chromatography-mass spectrometry based metabolomic approach. Seven polar and 83 non-polar (lipids) metabolites in plasma were significantly different (false discovery rate < 0.05) between milk treatments. These included polar metabolites involved in amino acid metabolism and lipids belonging to phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, and triglycerides. Compared to the caprine or bovine milk group, the relative intensities of polar metabolites and unsaturated triglycerides were higher in the peripheral circulation of the ovine milk group. In contrast, relative intensities of saturated triglycerides and phosphatidylcholine were higher in the bovine milk group compared to the ovine or caprine milk group. In addition, correlations were identified between amino acid and lipid intake and their appearance in peripheral blood circulation. The results highlighted that consuming different ruminants' milk influences the plasma appearance of metabolites, especially lipids, that may contribute to early postnatal life development in pigs.

Human sphingomyelin synthase 1 generates diacylglycerol in the presence and absence of ceramide via multiple enzymatic activities.

Sphingomyelin (SM) synthase 1 (SMS1), which is involved in lipodystrophy, deafness, and thrombasthenia, generates diacylglycerol (DG) and SM using phosphatidylcholine (PC) and ceramide as substrates. Here, we found that SMS1 possesses DG-generating activities via hydrolysis of PC and phosphatidylethanolamine (PE) in the absence of ceramide and ceramide phosphoethanolamine synthase (CPES) activity. In the presence of the same concentration (4.7 mol%) of PC and ceramide, the amounts of DG produced by SMS and PC-phospholipase C (PLC) activities of SMS1 were approximately 65% and 35% of total DG production, respectively. PC-PLC activity showed substrate selectivity for saturated and/or monounsaturated fatty acid-containing PC species. A PC-PLC/SMS inhibitor, D609, inhibited only SMS activity. Mn2+ inhibited only PC-PLC activity. Intriguingly, DG attenuated SMS/CPES activities. Our study indicates that SMS1 is a unique enzyme with PC-PLC/PE-PLC/SMS/CPES activities.

Dietary Eicosapentaenoic Acid Containing Phosphoethanolamine Plasmalogens Remodels the Lipidome of White Adipose Tissue and Suppresses High-Fat Diet Induced Obesity in Mice.

Dietary supplementation of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) can alter the lipidome profiles of adipocytes, thereby counteract obesity. DHA/EPA in the form of phospholipids demonstrates higher bioavailability than triglyceride or ethyl ester (EE), but their effects on the lipidome and metabolic changes during obesity are still unknown. High-fat diet-induced obese mice are treated with different molecular forms of EPA, and EPA supplemented as phosphoethanolamine plasmalogens (PlsEtn) has a superior effect on reducing fat mass accumulation than phosphatidylcholine (PC) or EE. The lipidomics analysis indicates that EPA in form of PlsEtn but not PC or EE significantly decreases total PC and sphingomyelin content in white adipose tissue (WAT). Some specific polyunsaturated fatty acid -containing PCs and ether phospholipids are increased in EPA-PlsEtn-fed mice, which may attribute to the upregulation of unsaturated fatty acid biosynthesis and fatty acid elongation reactions in WAT. In addition, the expression of genes related to fatty acid catabolism is also promoted by EPA-PlsEtn supplementation, which may cause the decreased content of saturated and monounsaturated fatty acid-containing PCs. EPA-PlsEtn supplementation is demonstrated to remodel lipidome and regulate the fatty acid metabolic process in WAT, indicating it may serve as a new strategy for obesity treatment in the future.

Metabolomics and Lipidomics Studies in Pediatric Type 1 Diabetes: Biomarker Discovery for the Early Diagnosis and Prognosis

Aim. Type 1 diabetes (T1D) is an autoimmune disease with heterogeneous risk factors. Metabolic perturbations in the pathogenesis of the disease are remarkable to illuminate the interaction between genetic and environmental factors and how islet immunity and overt diabetes develop. This review aimed to integrate the metabolic changes of T1D to identify potential biomarkers for predicting disease progression based on recent metabolomics and lipidomics studies with parallel methodologies. Methods. A total of 18 metabolomics and lipidomics studies of childhood T1D during the last 15 years were reviewed. The metabolic fingerprints consisting of 41 lipids and/or metabolite classes of subjects with islet autoantibodies, progressors of T1D, and T1D children were mapped in four-time dimensions based on a tentative effect-score rule. Results. From birth, high-risk T1D subjects had decreased unsaturated triacylglycerols, unsaturated phosphatidylcholines (PCs), sphingomyelins (SMs), amino acids, and metabolites in the tricarboxylic acid (TCA) cycle. On the contrary, lysophosphatidylcholines (LPCs) and monosaccharides increased. And LPCs and branched-chain amino acids (BCAAs) were elevated before the appearance of islet autoantibodies but were lowered after seroconversion. Choline-related lipids (including PCs, SMs, and LPCs), BCAAs, and metabolites involved in the TCA cycle were identified as consensus biomarkers potentially predicting the development of islet autoimmunity and T1D. Decreased LPCs and amino acids indicated poor glycemic control of T1D, while elevated lysophosphatidylethanolamines and saturated PCs implied good glycemic control. Further pathway analysis revealed that biosynthesis of aminoacyl-tRNA, BCAAs, and alanine, aspartate, and glutamate metabolism were significantly enriched. Moreover, established cohort studies and predictive statistical models of pediatric T1D were also summarized. Conclusion. The metabolic profile of high-risk T1D subjects and patients demonstrated significant changes compared with healthy controls. This integrated analysis provides a comprehensive overview of metabolic features and potential biomarkers in the pathogenesis and progression of T1D.

Lipid composition remodeling plays a critical role during the differential responses of leaves and roots to heat stress in bermudagrass

Heat stress is one of the most detrimental abiotic stresses to impede plant growth and development. Previous studies found that plant roots were more sensitive to heat stress than leaves. However, the underlying mechanisms remain unclear. The objective of this study was to determine whether the differential responses of leaves and roots to heat stress were associated with membrane lipid reprogramming under heat stress. Bermudagrass (Cynodon transvaalensis × C. dactylon) was subjected to control (35/30 °C day/night) or heat stress (45/40 °C day/night) in growth chambers. Phenotype and physiological indexes of bermudagrass were observed and measured at 0, 12, and 24 d and lipidomic analysis was conducted at 24 d of heat stress. After 12 d of heat stress, roots exhibited worse phenotypes with higher decline in biomass and increase in both electrolyte leakage and malondialdehyde compared to leaves. Lipidomic analysis showed that leaves have more stable membrane structures than roots in response to heat stress, which was attributed to the up-regulation of phosphatidylglycerol, monogalactosyl diacylglycerol, digalactosyl diacylglycerol, phosphatidic acid, phosphatidylinositol, and saturated and low unsaturated phosphatidylcholine and phosphatidylethanolamine, as well as the down-regulation in polyunsaturated phosphatidylcholine and phosphatidylethanolamine in leaves, therefore resulting in the greater heat tolerance in leaves than roots. These results indicated that the differential responses of leaves and roots to heat stress were involved in the membrane lipid remodeling.

L-Phenylalanine Partitioning Mechanisms in Model Biological Membranes.

Time-resolved fluorescence spectroscopy in combination with differential scanning calorimetry (DSC) was used to study the chemical interactions that occur when l-phenylalanine is introduced to solutions containing phosphatidylcholine vesicles. Studies reported in this work address open questions about l-Phe's affinity for lipid vesicle bilayers, the effects of l-Phe partitioning on bilayer properties, l-Phe's solvation within a lipid bilayer, and the amount of l-Phe within that local solvation environment. DSC data show that l-Phe reduces the amount of heat necessary to melt saturated phosphatidylcholine bilayers from their gel to liquid-crystalline state but does not change the transition temperature (Tgel-lc). Time-resolved emission shows only a single l-Phe lifetime at low temperatures corresponding to l-Phe remaining solvated in aqueous solution. At temperatures close to Tgel-lc, a second, shorter lifetime appears that is assigned to l-Phe already embedded within the membrane that becomes hydrated as water starts to permeate the lipid bilayer. This new lifetime is attributed to a conformationally restricted rotamer in the bilayer's polar headgroup region and accounts for up to 30% of the emission amplitude. Results reported for dipalmitoylphosphatidylcholine (DPPC, 16:0) lipid vesicles prove to be general, with similar effects observed for dimyristoylphosphatidylcholine (DMPC, 14:0) and distearoylphosphatidylcholine (DSPC, 18:0) vesicles. Taken together, these results create a complete and compelling picture of how l-Phe associates with model biological membranes. Furthermore, this approach to examining amino acid partitioning into membranes and the resulting solvation forces points to new strategies for studying the structure and chemistry of membrane-soluble peptides and selected membrane proteins.

LPCAT1 levels in the placenta, the maternal plasma and the fetal plasma do not predict fetal lung responses to glucocorticoids in a sheep model of pregnancy

IntroductionLysophosphatidylcholine acyltransferase 1 (LPCAT1) is important for saturated phosphatidylcholine (Sat-PC) production in the lung. Sat-PC is a critical component of pulmonary surfactant, which maintains low alveolar surface tension, facilitating respiration. Previous studies have reported an association between maternal and fetal LPCAT1 levels and neonatal lung function. Using a sheep model of pregnancy, we investigated a potential correlation between glucocorticoid-induced lung maturation and LPCAT1 mRNA and/or protein levels in the fetal lung, the placenta, the fetal plasma, and the maternal plasma. MethodsEighty seven single pregnant ewes received maternal intramuscular injections of betamethasone. A sub-group of five animals had both maternal and fetal catheters installed to allow for sequential sampling from both plasma compartments. Lambs were surgically delivered under terminal anaesthesia between 2 and 8 days after initial ANS treatment, at a gestational age of 121–123 days. Lambs were ventilated for 30 min to determine functional lung maturation before being euthanized for necropsy and sample collection. Fetal lung, placenta, and fetal and maternal plasma samples were used to analyse LPCAT1 gene expression and protein levels. ResultsThe expression of LPCAT1 mRNA in the fetal lung was significantly corelated to Sat-PC levels at 8 days (R2 = 0.23, p < 0.001) and lung maturation status overall (gas exchange efficiency as determined by measurements of lamb PaCO2 during ventilation, R2 = 0.20, p < 0.001). Similarly, fetal lung LPCAT1 mRNA was also significantly correlated with the individual durability of ANS effects on fetal lung maturation (R2 = 0.20, p < 0.001). Although ANS therapy altered LPCAT1 mRNA expression in the placenta, observed changes were independent of fetal lung maturation outcomes. Neither maternal nor fetal plasma LPCAT1 levels were changed by ANS therapy over the period, including in analysis of serial maternal and fetal samples from chronically catheterised animals. DiscussionLPCAT1 expression in the fetal lung was associated with the durability of glucocorticoid effects on fetal lung maturation. However, LPCAT1 expression in the placenta, the fetal plasma, and the maternal plasma was neither associated with, nor predictive of fetal lung maturation after glucocorticoid treatment in a sheep model of pregnancy.

Lipidomic profiling of rat hepatic stellate cells during activation reveals a two-stage process accompanied by increased levels of lysosomal lipids

Hepatic stellate cells (HSCs) are liver-resident cells best known for their role in vitamin A storage under physiological conditions. Upon liver injury, HSCs activate into myofibroblast-like cells, a key process in the onset of liver fibrosis. Lipids play an important role during HSC activation. Here, we provide a comprehensive characterization of the lipidomes of primary rat HSCs during 17days of activation invitro. For lipidomic data interpretation, we expanded our previously described Lipid Ontology (LION) and associated web application (LION/Web) with the LION-PCA heatmap module, which generates heatmaps of the most typical LION-signatures in lipidomic datasets. Furthermore, we used LION to perform pathway analysis to determine the significant metabolic conversions in lipid pathways. Together, we identify two distinct stages of HSC activation. In the first stage, we observe a decrease of saturated phosphatidylcholine, sphingomyelin, and phosphatidic acid and an increase in phosphatidylserine and polyunsaturated bis(monoacylglycero)phosphate (BMP), a lipid class typically localized at endosomes and lysosomes. In the second activation stage, BMPs, hexosylceramides, and ether-linked phosphatidylcholines are elevated, resembling a lysosomal lipid storage disease profile. The presence of isomeric structures of BMP in HSCs was confirmed exvivo in MS-imaging datasets of steatosed liver sections. Finally, treatment with pharmaceuticals targeting the lysosomal integrity led to cell death in primary HSCs but not in HeLa cells. In summary, our combined data suggest that lysosomes play a critical role during a two-stage activation process of HSCs.

Temperature-Dependent Re-alignment of the Short Multifunctional Peptide BP100 in Membranes Revealed by Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

BP100 is a cationic undecamer peptide with antimicrobial and cell-penetrating activities. The orientation of this amphiphilic α-helix in lipid bilayers was examined under numerous conditions using solid-state 19 F, 15 N and 2 H NMR. At high temperatures in saturated phosphatidylcholine lipids, BP100 lies flat on the membrane surface, as expected. Upon lowering the temperature towards the lipid phase transition, the helix is found to flip into an upright transmembrane orientation. In thin bilayers, this inserted state was stable at low peptide concentration, but thicker membranes required higher peptide concentrations. In the presence of lysolipids, the inserted state prevailed even at high temperature. Molecular dynamics simulations suggest that BP100 monomer insertion can be stabilized by snorkeling lysine side chains. These results demonstrate that even a very short helix like BP100 can span (and thereby penetrate through) a cellular membrane under suitable conditions.

The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma.

Metabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.

Structural determinants of REMORIN nanodomain formation in anionic membranes

Remorins are a family of multigenic plasma membrane phosphoproteins involved in biotic and abiotic plant interaction mechanisms, partnering in molecular signaling cascades. Signaling activity of remorins depends on their phosphorylation states and subsequent clustering into nanosized membrane domains. The presence of a coiled-coil domain and a C-terminal domain is crucial to anchor remorins to negatively charged membrane domains; however, the exact role of the N-terminal intrinsically disordered domain (IDD) on protein clustering and lipid interactions is largely unknown. Here, we combine chemical biology and imaging approaches to study the partitioning of group 1 remorin into anionic model membranes mimicking the inner leaflet of the plant plasma membrane. Using reconstituted membranes containing a mix of saturated and unsaturated phosphatidylcholine, phosphatidylinositol phosphates, and sterol, we investigate the clustering of remorins to the membrane and monitor the formation of nanosized membrane domains. REM1.3 promoted membrane nanodomain organization on the exposed external leaflet of both spherical lipid vesicles and flat supported lipid bilayers. Our results reveal that REM1.3 drives a mechanism allowing lipid reorganization, leading to the formation of remorin-enriched nanodomains. Phosphorylation of the N-terminal IDD by the calcium protein kinase CPK3 influences this clustering and can lead to the formation of smaller and more disperse domains. Our work reveals the phosphate-dependent involvement of the N-terminal IDD in the remorin-membrane interaction process by driving structural rearrangements at lipid-water interfaces.

Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD.

Perfluorooctanoic Acid-Disturbed Serum and Liver Lipidome in C57BL/6 Mice

Perfluorooctanoic acid is a manufactured material extensively utilized in industrial and consumer products. As a persistent organic pollutant, perfluorooctanoic acid has raised increasing public health concerns recently. Although perfluorooctanoic acid is known to induce lipid accumulation in the liver, the impact of perfluorooctanoic acid on different lipid classes has not been fully evaluated. In this study, we performed untargeted lipidomics analysis to investigate the impact of perfluorooctanoic acid on the lipid homeostasis in C57BL/6 male mice. Perfluorooctanoic acid disturbed the lipid profiles in serum and liver, with a variety of lipid classes significantly altered. Greater impacts were observed in the liver lipidome than the serum lipidome. In particular, some lipid clusters in the liver were altered by both high- and low-dose perfluorooctanoic acid exposure, including the increase of unsaturated triglycerides and the decrease of sphingomyelins, saturated phosphatidylcholines, saturated lysophosphatidylcholines, and phospholipid ethers. In parallel with an increase in the liver, a decrease of saturated phosphatidylcholines was found in the serum of high-dose perfluorooctanoic acid-treated mice. The findings from this study are helpful to improve the understanding of perfluorooctanoic acid-induced dysregulation of lipid metabolism and perfluorooctanoic acid-associated health effects in liver.

A mass spectrometry imaging and lipidomic investigation reveals aberrant lipid metabolism in the orthotopic mouse glioma

Lipids perform multiple biological functions and reflect the physiology and pathology of cells, tissues, and organs. Here, we sought to understand lipid content in relation to tumor pathology by characterizing phospholipids and sphingolipids in the orthotopic mouse glioma using MALDI MS imaging (MSI) and LC-MS/MS. Unsupervised clustering analysis of the MALDI-MSI data segmented the coronal tumoral brain section into 10 histopathologically salient regions. Heterogeneous decrease of the common saturated phosphatidylcholines (PCs) in the tumor was accompanied by the increase of analogous PCs with one or two additional fatty acyl double bonds and increased lyso-PCs. Polyunsaturated fatty acyl-PCs and ether PCs highlighted the striatal tumor margins, whereas the distributions of other PCs differentiated the cortical and striatal tumor parenchyma. We detected a reduction of SM d18:1/18:0 and the heterogeneous mild increase of SM d18:1/16:0 in the tumor, whereas ceramides accumulated only in a small patch deep in the tumoral parenchyma. LC-MS/MS analyses of phospholipids and sphingolipids complemented the MALDI-MSI observation, providing a snapshot of these lipids in the tumor. Finally, the proposed mechanisms responsible for the tumoral lipid changes were contrasted with our interrogation of gene expression in human glioma. Together, these lipidomic results unveil the aberrant and heterogeneous lipid metabolism in mouse glioma where multiple lipid-associated signaling pathways underline the tumor features, promote the survival, growth, proliferation, and invasion of different tumor cell populations, and implicate the management strategy of a multiple-target approach for glioma and related brain malignancies.

Behavior of Triterpenoid Saponin Ginsenoside Rh2 in Ordered and Disordered Phases in Model Membranes Consisting of Sphingomyelin, Phosphatidylcholine, and Cholesterol.

The ginsenoside Rh2 (Rh2) is a saponin of medicinal ginseng, and it has attracted much attention for its pharmacological activities. In this study, we investigated the interaction of Rh2 with biological membranes using model membranes. We examined the effects of various lipids on the membrane-disrupting activity of Rh2 and found that cholesterol and sphingomyelin (SM) had no significant effect. Furthermore, the effects of Rh2 on acyl chain packing (DPH anisotropy) and water molecule permeability (GP340 values) did not differ significantly between bilayers containing SM and saturated phosphatidylcholine. These results suggest that the formation of the liquid-ordered (Lo) phase affects the behavior of Rh2 in the membrane rather than a specific interaction of Rh2 with a particular lipid. We investigated the effects of Rh2 on the Lo and liquid-disordered (Ld) phases using surface tension measurements and fluorescence experiments. In the surface tension-area isotherms, we compared the monolayers of the Ld and Lo lipid compositions and found that Rh2 is abundantly bound to both monolayers, with the amount being greater in the Ld phase than in the Lo phase. In addition, the hydration state of the bilayers, mainly consisting of the Lo or Ld phase, showed that Rh2 tends to bind to the surface of the bilayer in both phases. At higher concentrations, Rh2 tends to bind more abundantly to the relatively shallow interior of the Ld phase than the Lo phase. The phase-dependent membrane behavior of Rh2 is probably due to the phase-selective affinity and binding mode of Rh2.

Exploring the binding kinetics and behaviors of self-aggregated beta-amyloid oligomers to phase-separated lipid rafts with or without ganglioside-clusters

Lipid binding kinetics and energetics of self-aggregated and disordered beta-amyloid oligomers of various sizes, from solution to lipid raft surfaces, were investigated using MD simulations. Our systems include small (monomers to tetramers) and larger (octamers and dodecamers) oligomers. Our lipid rafts contain saturated and unsaturated phosphatidylcholine (PC), cholesterol, and with or without asymmetrically distributed monosialotetrahexosylganglioside (GM1). All rafts exhibited dynamic and structurally diversified domains including liquid-ordered (Lo), liquid-disordered (Ld), and interfacial Lod domains. For rafts without GM1, all oligomers bound to the Lod domain. For GM1-containing rafts, all small oligomers and most larger oligomers bound specifically to the GM1-clusters embedded in the Lo domain. Lipid-protein binding energies followed an order of GM1 >> unsaturated PC > saturated PC > cholesterol for all rafts. In addition, protein-induced membrane structural disruption increased progressively with the size of the oligomer for the annular lipids surrounding the membrane-bound protein in non-GM1-containing rafts. We propose that the tight binding of beta-amyloid oligomers to the GM1-clusters and the structural perturbation of lipids surrounding the membrane-bound proteins at the Lod domain are early molecular events of the beta-amyloid aggregation process on neuronal membrane surfaces that trigger the onset of Alzheimer's.