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Cell Host & Microbe Mar 2024Phosphatidic acid (PA) and reactive oxygen species (ROS) are cellular messengers that relay signals to regulate diverse biological processes. In recent issues of Cell...
Phosphatidic acid (PA) and reactive oxygen species (ROS) are cellular messengers that relay signals to regulate diverse biological processes. In recent issues of Cell Host & Microbe and Cell, Qi et al. and Kong et al., respectively, investigate diacylglycerol kinase 5-mediated PA in regulating ROS signaling and plant immunity.
Topics: Reactive Oxygen Species; Signal Transduction; Diacylglycerol Kinase; Phosphatidic Acids
PubMed: 38484710
DOI: 10.1016/j.chom.2024.02.005 -
Nature Communications Jul 2023A lipidome comprises thousands of lipid species, many of which are isomers and isobars. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), although widely used...
A lipidome comprises thousands of lipid species, many of which are isomers and isobars. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), although widely used for lipidomic profiling, faces challenges in differentiating lipid isomers. Herein, we address this issue by leveraging the orthogonal separation capabilities of hydrophilic interaction liquid chromatography (HILIC) and trapped ion mobility spectrometry (TIMS). We further integrate isomer-resolved MS/MS methods onto HILIC-TIMS, which enable pinpointing double bond locations in phospholipids and sn-positions in phosphatidylcholine. This system profiles phospholipids at multiple structural levels with short analysis time (<10 min per LC run), high sensitivity (nM detection limit), and wide coverage, while data analysis is streamlined using a home-developed software, LipidNovelist. Notably, compared to our previous report, the system doubles the coverage of phospholipids in bovine liver and reveals uncanonical desaturation pathways in RAW 264.7 macrophages. Relative quantitation of the double bond location isomers of phospholipids and the sn-position isomers of phosphatidylcholine enables the phenotyping of human bladder cancer tissue relative to normal control, which would be otherwise indistinguishable by traditional profiling methods. Our research offers a comprehensive solution for lipidomic profiling and highlights the critical role of isomer analysis in studying lipid metabolism in both healthy and diseased states.
Topics: Lipids; Animals; Cattle; Liver; Tandem Mass Spectrometry; Phospholipids; Mice; RAW 264.7 Cells; Humans; Chromatography, Liquid; Phosphatidylcholines; Software; Glycerophospholipids; Sphingomyelins; Urinary Bladder Neoplasms
PubMed: 37460558
DOI: 10.1038/s41467-023-40046-x -
Alteration of Meibum Lipidomics Profiling in Patients With Chronic Ocular Graft-Versus-Host Disease.Investigative Ophthalmology & Visual... Sep 2023To investigate the characteristics of the lipid profiling in meibum of patients with chronic ocular graft-versus-host disease (coGVHD) and to detect the potential...
PURPOSE
To investigate the characteristics of the lipid profiling in meibum of patients with chronic ocular graft-versus-host disease (coGVHD) and to detect the potential influence of anti-inflammatory therapy on these differential lipids.
METHODS
This cross-sectional study included 25 coGVHD patients and 13 non-coGVHD after allogeneic hematopoietic stem cell transplantation. Among those with coGVHD, 14 had prior topical treatment (coGVHD(T)), and 11 did not (coGVHD(WT)). All participants completed ocular surface disease index questionnaire and received slit lamp examination, Schirmer's test without anesthesia, ocular surface interferometer, and meibography. Binocular meibum was collected and pooled for lipidomic analysis by liquid chromatography-mass spectrometry.
RESULTS
One hundred and twenty differential lipid species were found among the three groups (96 of coGVHD(WT) vs. non-coGVHD, 78 of coGVHD(WT) vs. coGVHD(T), and three of non-coGVHD vs. coGVHD(T)). Compared with non-coGVHD group, coGVHD(WT) group had a significant abnormality of meibum composition, showing a significant decrease in glycerolipids, and an increase in glycerophospholipids and sphingolipids. Similar changes were also observed when coGVHD(WT) versus coGVHD(T). CoGVHD severity was negatively associated with mono-unsaturated triglycerides (TG), (β = -214.7; 95% CI, -363.9 to -65.5; P = 0.006) and poly-unsaturated TG (β = -4019.9; 95% CI, -7758.1 to -281.6; P = 0.036). Intensity of immunosuppression was negatively associated with mono-unsaturated TG (β = -162.4; 95% CI, -268.6 to -56.2; P = 0.004) and positively associated with phosphatidylcholine (β = 332.0; 95% CI, 19.2-644.8; P = 0.038).
CONCLUSIONS
Altered meibum in coGVHD is characterized by a decrease of glycerolipids and an increase of glycerophospholipids and may be significantly reversed by topical anti-inflammatory therapy.
Topics: Humans; Cross-Sectional Studies; Lipidomics; Tears; Graft vs Host Disease; Glycerophospholipids
PubMed: 37733365
DOI: 10.1167/iovs.64.12.35 -
PLoS Biology Dec 2023Lysophosphatidylserine (LysoPS) is a naturally occurring lipid mediator involved in various physiological and pathological processes especially those related to the...
Lysophosphatidylserine (LysoPS) is a naturally occurring lipid mediator involved in various physiological and pathological processes especially those related to the immune system. GPR34, GPR174, and P2Y10 have been identified as the receptors for LysoPS, and its analogues have been developed as agonists or antagonists for these receptors. However, the lack of structural information hinders the drug development with novel characteristics, such as nonlipid ligands and allosteric modulators. Here, we determined the structures of human GPR34 and GPR174 in complex with LysoPS and G protein by cryo-EM. Combined with structural analysis and functional studies, we elucidated the lipid-binding modes of these receptors. By structural comparison, we identified the structural features of GPR34 and GPR174 in active state. Taken together, our findings provide insights into ligand recognition and signaling of LysoPS receptors and will facilitate the development of novel therapeutics for related inflammatory diseases and autoimmune diseases.
Topics: Humans; Ligands; Lysophospholipids; Receptors, G-Protein-Coupled; Receptors, Lysophospholipid
PubMed: 38048360
DOI: 10.1371/journal.pbio.3002387 -
Molecules (Basel, Switzerland) Jul 2023Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol... (Review)
Review
Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from (PC-PLC). Nonetheless, there is evidence for PC-PLC activity as a human functional equivalent of its prokaryotic counterpart. Additionally, inhibitors of PC-PLC have been developed as potential therapeutic agents. The most notable classes include 2-aminohydroxamic acids, xanthates, ,'-hydroxyureas, phospholipid analogues, 1,4-oxazepines, pyrido[3,4-]indoles, morpholinobenzoic acids and univalent ions. However, many medicinal chemistry studies lack evidence for their cellular and in vivo effects, which hampers the progression of the inhibitors towards the clinic. This review outlines the pathological implications of PC-PLC and highlights current progress and future challenges in the development of PC-PLC inhibitors from the literature.
Topics: Humans; Type C Phospholipases; Phosphatidylcholines
PubMed: 37570610
DOI: 10.3390/molecules28155637 -
Cell Host & Microbe Mar 2024In plant immunity, phosphatidic acid (PA) regulates reactive oxygen species (ROS) by binding to respiratory burst oxidase homolog D (RBOHD), an NADPH oxidase responsible...
In plant immunity, phosphatidic acid (PA) regulates reactive oxygen species (ROS) by binding to respiratory burst oxidase homolog D (RBOHD), an NADPH oxidase responsible for ROS production. Here, we analyze the influence of PA binding on RBOHD activity and the mechanism of RBOHD-bound PA generation. PA binding enhances RBOHD protein stability by inhibiting vacuolar degradation, thereby increasing chitin-induced ROS production. Mutations in diacylglycerol kinase 5 (DGK5), which phosphorylates diacylglycerol to produce PA, impair chitin-induced PA and ROS production. The DGK5 transcript DGK5β (but not DGK5α) complements reduced PA and ROS production in dgk5-1 mutants, as well as resistance to Botrytis cinerea. Phosphorylation of S506 residue in the C-terminal calmodulin-binding domain of DGK5β contributes to the activation of DGK5β to produce PA. These findings suggest that DGK5β-derived PA regulates ROS production by inhibiting RBOHD protein degradation, elucidating the role of PA-ROS interplay in immune response regulation.
Topics: Arabidopsis Proteins; Reactive Oxygen Species; Phosphatidic Acids; NADPH Oxidases; Plant Immunity; Chitin; Gene Expression Regulation, Plant
PubMed: 38309260
DOI: 10.1016/j.chom.2024.01.011 -
The Journal of Cell Biology Aug 2023The maintenance of plasma membrane integrity and a capacity for efficiently repairing damaged membranes are essential for cell survival. Large-scale wounding depletes...
The maintenance of plasma membrane integrity and a capacity for efficiently repairing damaged membranes are essential for cell survival. Large-scale wounding depletes various membrane components at the wound sites, including phosphatidylinositols, yet little is known about how phosphatidylinositols are generated after depletion. Here, working with our in vivo C. elegans epidermal cell wounding model, we discovered phosphatidylinositol 4-phosphate (PtdIns4P) accumulation and local phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] generation at the wound site. We found that PtdIns(4,5)P2 generation depends on the delivery of PtdIns4P, PI4K, and PI4P 5-kinase PPK-1. In addition, we show that wounding triggers enrichment of the Golgi membrane to the wound site, and that is required for membrane repair. Moreover, genetic and pharmacological inhibitor experiments support that the Golgi membrane provides the PtdIns4P for PtdIns(4,5)P2 generation at the wounds. Our findings demonstrate how the Golgi apparatus facilitates membrane repair in response to wounding and offers a valuable perspective on cellular survival mechanisms upon mechanical stress in a physiological context.
Topics: Animals; Caenorhabditis elegans; Cell Membrane; Golgi Apparatus; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Stress, Mechanical
PubMed: 37158801
DOI: 10.1083/jcb.202303017 -
Lipids in Health and Disease May 2024Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction,... (Review)
Review
Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.
Topics: Humans; Prognosis; Neoplasms; Lipidomics; Biomarkers, Tumor; Mass Spectrometry; Female; Lipids; Male; Breast Neoplasms; Prostatic Neoplasms; Lysophospholipids; Colorectal Neoplasms
PubMed: 38796445
DOI: 10.1186/s12944-024-02121-0 -
Cell Reports Nov 2023Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form...
Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.
Topics: Humans; Animals; Mice; Phosphatidylglycerols; Hearing Loss, Sensorineural; Metabolism, Inborn Errors; Deafness; Cardiolipins
PubMed: 37917582
DOI: 10.1016/j.celrep.2023.113214 -
Immunological Reviews Aug 2023The pulmonary surfactant system of the lung is a lipid and protein complex, which regulates the biophysical properties of the alveoli to prevent lung collapse and the... (Review)
Review
The pulmonary surfactant system of the lung is a lipid and protein complex, which regulates the biophysical properties of the alveoli to prevent lung collapse and the innate immune system in the lung. Pulmonary surfactant is a lipoprotein complex consisting of 90% phospholipids and 10% protein, by weight. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), exist at very high concentrations in the extracellular alveolar compartments. We have reported that one of the most dominant molecular species of PG, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and PI inhibit inflammatory responses induced by multiple toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6) by interacting with subsets of multiprotein receptor components. These lipids also exert potent antiviral effects against RSV and influenza A, in vitro, by inhibiting virus binding to host cells. POPG and PI inhibit these viral infections in vivo, in multiple animal models. Especially noteworthy, these lipids markedly attenuate SARS-CoV-2 infection including its variants. These lipids are natural compounds that already exist in the lung and, thus, are less likely to cause adverse immune responses by hosts. Collectively, these data demonstrate that POPG and PI have strong potential as novel therapeutics for applications as anti-inflammatory compounds and preventatives, as treatments for broad ranges of RNA respiratory viruses.
Topics: Animals; Humans; Phospholipids; Pulmonary Surfactants; Antiviral Agents; Toll-Like Receptor 2; COVID-19; SARS-CoV-2; Lung; Anti-Inflammatory Agents; Phosphatidylglycerols
PubMed: 37144896
DOI: 10.1111/imr.13207