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Proceedings of the National Academy of... Dec 2023AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the gene cause the most...
Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition.
AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the gene cause the most common form of congenital generalized lipodystrophy which leads to steatohepatitis. The underlying mechanism by which AGPAT2 deficiency leads to lipodystrophy and steatohepatitis has not been elucidated. We addressed this question using an antisense oligonucleotide (ASO) to knockdown expression of in the liver and white adipose tissue (WAT) of adult male Sprague-Dawley rats. ASO treatment induced lipodystrophy and inflammation in WAT and the liver, which was associated with increased LPA content in both tissues, whereas PA content was unchanged. We found that a controlled-release mitochondrial protonophore (CRMP) prevented LPA accumulation and inflammation in WAT whereas an ASO against () prevented LPA content and inflammation in the liver in ASO-treated rats. In addition, we show that overnutrition, due to high sucrose feeding, resulted in increased hepatic LPA content and increased activated macrophage content which were both abrogated with ASO treatment. Taken together, these data identify LPA as a key mediator of liver and WAT inflammation and lipodystrophy due to AGPAT2 deficiency as well as liver inflammation due to overnutrition and identify LPA as a potential therapeutic target to ameliorate these conditions.
Topics: Male; Rats; Animals; Acyltransferases; Glycerol; 1-Acylglycerol-3-Phosphate O-Acyltransferase; Rats, Sprague-Dawley; Lipodystrophy; Fatty Liver; Adipose Tissue, White; Phosphatidic Acids; Inflammation; Overnutrition; Phosphates
PubMed: 38127985
DOI: 10.1073/pnas.2312666120 -
Bioorganic & Medicinal Chemistry Oct 2023Phosphatidylinositol transfer proteins (PITPs) are ubiquitous in eukaryotes and are involved in the regulation of phospholipid metabolism, membrane trafficking, and...
Phosphatidylinositol transfer proteins (PITPs) are ubiquitous in eukaryotes and are involved in the regulation of phospholipid metabolism, membrane trafficking, and signal transduction. Sec14 is a yeast PITP that has been shown to transfer phosphatidylinositol (PI) or phosphatidylcholine (PC) from the endoplasmic reticulum to the Golgi. It is now believed that Sec14 may play a greater role than just shuttling PI and PC throughout the cell. Genetic evidence suggests that retrieval of membrane-bound PI by Sec14 also manages to present PI to the phosphatidylinositol-4-kinase, Pik1, to generate phosphatidylinositol-4-phosphate, PI(4)P. To test this hypothetical model, we designed a photocleavable bolalipid to span the entire membrane, having one phosphatidylcholine or phosphatidylinositol headgroup on each leaflet connected by a photocleavable diacid. Sec14 should not be able to present the bola-PI to Pik1 for phosphorylation as the head group will be difficult to lift from the bilayer as it is tethered on the opposite leaflet. After photocleavage the two halves would behave as a normal phospholipid, thus phosphorylation by Pik1 would resume. We report here the synthesis of a photocleavable bola-PC, a precursor to the desired bola-PI. The mono-photocleavable bola-PC lipid was designed to contain two glycerol molecules with choline head groups connected through a phosphodiester bond at the sn3 position. Each glycerol was acylated with palmitic acid at the sn1 position. These two glycerol moieties were then connected through their respective sn2 hydroxyls via a photocleavable dicarboxylic acid containing a nitrophenyl ethyl photolabile protecting group. The bola-PC and its precursors were found to undergo efficient photocleavage when irradiated in solution or in vesicles with 365 nm light for two minutes. Treatment of the bola-PC with a mutant phospholipase D and myo-inositol produced a mono-inositol bola-PC-PI.
Topics: Phosphatidylcholines; Glycerol; Phosphorylation; Phospholipids; Phosphatidylinositols
PubMed: 37688997
DOI: 10.1016/j.bmc.2023.117465 -
Journal of the American Chemical Society Oct 2023Coley's toxins, an early and enigmatic form of cancer (immuno)therapy, were based on preparations of . As part of a program to explore bacterial metabolites with...
Coley's toxins, an early and enigmatic form of cancer (immuno)therapy, were based on preparations of . As part of a program to explore bacterial metabolites with immunomodulatory potential, . metabolites were assayed in a cell-based immune assay, and a single membrane lipid, 18:1/18:0/18:1/18:0 cardiolipin, was identified. Its activity was profiled in additional cellular assays, which showed it to be an agonist of a TLR2-TLR1 signaling pathway with a 6 μM EC and robust TNF-α induction. A synthetic analog with switched acyl chains had no measurable activity in immune assays. The identification of a single immunogenic cardiolipin with a restricted structure-activity profile has implications for immune regulation, cancer immunotherapy, and poststreptococcal autoimmune diseases.
Topics: Humans; Streptococcus pyogenes; Cardiolipins; Neoplasms; Tumor Necrosis Factor-alpha
PubMed: 37738205
DOI: 10.1021/jacs.3c07727 -
Brain Research Nov 2023Effective blood coagulation prevents inflammation and neuronal loss after brain injury. 2-Carba-cyclic phosphatidic acid (2ccPA), a biotherapeutic for brain injury,...
Effective blood coagulation prevents inflammation and neuronal loss after brain injury. 2-Carba-cyclic phosphatidic acid (2ccPA), a biotherapeutic for brain injury, inhibits blood extravasation resulting from blood-brain barrier breakdown. However, the hemostasis mechanism of 2ccPA remains unclear. We determined the effects of 2ccPA-injection on blood coagulation and fibrinolysis using a needle-induced brain injury model. 2ccPA suppressed the expression of platelet degranulation-related genes. Immediately after brain injury, 2ccPA increased CD41 platelet aggregation around the lesions and promoted fibrin aggregation. Additionally, 2ccPA supported fibrinolysis by upregulating plasminogen activator expression. These results suggest the acute effects of 2ccPA on brain hemostasis.
Topics: Humans; Fibrinolysis; Phosphatidic Acids; Blood Coagulation; Brain Injuries
PubMed: 37506965
DOI: 10.1016/j.brainres.2023.148511 -
The Journal of Organic Chemistry Aug 2023Glycerophospholipids are major components of cellular membranes and provide important signaling molecules. Besides shaping membrane properties, some bind to specific...
Glycerophospholipids are major components of cellular membranes and provide important signaling molecules. Besides shaping membrane properties, some bind to specific receptors to activate biological pathways. Untangling the roles of individual glycerophospholipids requires clearly defined molecular species, a challenge that can be best addressed through chemical synthesis. However, glycerophospholipid syntheses are often lengthy due to the contrasting polarities found within these lipids. We now report a general strategy to quickly access glycerophospholipids via opening of a phosphate triester epoxide with carboxylic acids catalyzed by Jacobsen's Co(salen) complex. We show that this method can be applied to a variety of commercially available fatty acids, photoswitchable fatty acids, and other carboxylic acids to provide the corresponding glycerophosphate derivatives.
Topics: Glycerophospholipids; Fatty Acids; Cell Membrane; Carboxylic Acids
PubMed: 36449029
DOI: 10.1021/acs.joc.2c02096 -
The Journal of Cell Biology Sep 2023The lipid phosphatidylinositol 3,5-bisphosphate-PI(3,5)P2-is known to be a key regulator of cellular traffic in health and disease, but its cellular localization was...
The lipid phosphatidylinositol 3,5-bisphosphate-PI(3,5)P2-is known to be a key regulator of cellular traffic in health and disease, but its cellular localization was somewhat enigmatic until now, with the discovery of a new PI(3,5)P2 biosensor reported in this issue of JCB by Vines et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202209077).
Topics: Phosphatidylinositol Phosphates; Phosphatidylinositols; Biosensing Techniques
PubMed: 37578524
DOI: 10.1083/jcb.202308004 -
Lipids in Health and Disease Apr 2024This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach...
OBJECTIVE
This study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method.
METHOD
The study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The study assessed heterogeneity and horizontal pleiotropy through Cochran's Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study.
RESULTS
By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER BC), phosphatidylcholine (P < 0.05) and phosphatidylinositol (OR: 0.916-0.966, P < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P < 0.001) and triacylglycerol, OR: 0.894-0.960, P < 0.05)). However, the study did not observe a noteworthy impact of sphingolipids on ERBC. In the case of estrogen receptor-negative BC (ER BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P = 0.008), and glycerolipids (OR = 0.909, P = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034-1.056, P < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091-1.119, P < 0.05) was an important causal effect in ERBC.
CONCLUSIONS
The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the study elucidates BC's intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.
Topics: Bayes Theorem; Lipidomics; Mendelian Randomization Analysis; Glycerophospholipids; Phosphatidylinositols; Sphingolipids; Receptors, Estrogen; Genome-Wide Association Study; Neoplasms
PubMed: 38622701
DOI: 10.1186/s12944-024-02103-2 -
Bioorganic & Medicinal Chemistry Jul 2023The autoglobulin gene is the main enzyme for circulating LPA production and has lysophosphatidylcholine D activity, which catalyzes the production of lysophosphatidic... (Review)
Review
The autoglobulin gene is the main enzyme for circulating LPA production and has lysophosphatidylcholine D activity, which catalyzes the production of lysophosphatidic acid and choline with lysophosphatidylcholine as substrate. A growing body of experimental evidence suggests that autoglobulin is involved in the pathogenesis of a variety of diseases. This review summarizes the different structural ATX inhibitors classified according to their binding mode to the ATX triple orientation site, and summarizes the conformational relationships and molecular docking of each type with ATX structure, hoping to contribute to the development of novel ATX inhibitors.
Topics: Phosphoric Diester Hydrolases; Lysophosphatidylcholines; Molecular Docking Simulation; Lysophospholipids
PubMed: 37354726
DOI: 10.1016/j.bmc.2023.117374 -
Nutrients Jul 2023The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome...
The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome of adults with obesity before and after bariatric surgery. Ten pediatric (PE) and thirty adult (AD) patients with obesity were prospectively recruited at a referral single center. The PE cohort received lifestyle recommendations. The AD cohort underwent bariatric surgery. Clinical parameters and lipidome were analyzed in serum before and after six months of metabolic intervention. The abundance of phosphatidylinositols in the PE cohort and phosphatidylcholines in the AD significantly increased, while O-phosphatidylserines in the PE cohort and diacyl/triacylglycerols in the AD decreased. Fifteen lipid species were coincident in both groups after lifestyle intervention and bariatric surgery. Five species of phosphatidylinositols, sphingomyelins, and cholesteryl esters were upregulated. Eight species of diacylglycerols, glycerophosphoglycerols, glycerophosphoethanolamines, and phosphatidylcholines were downregulated. Most matching species were regulated in the same direction except for two phosphatidylinositols: PI(O-36:2) and PI(O-34:0). A specific set of lipid species regulated after bariatric surgery in adult individuals was also modulated in children undergoing lifestyle intervention, suggesting they may constitute a core circulating lipid profile signature indicative of early development of obesity and improvement after clinical interventions regardless of individual age.
Topics: Humans; Adult; Child; Pilot Projects; Pediatric Obesity; Lipidomics; Sphingomyelins; Phosphatidylcholines; Phosphatidylinositols
PubMed: 37571279
DOI: 10.3390/nu15153341 -
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