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International Journal of Molecular... Aug 2023Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of... (Review)
Review
Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P), both essential lipid mediators. These second messengers regulate the intracellular calcium (Ca) concentration, which activates signal transduction cascades involved in the regulation of cardiomyocyte activity. Of note, emerging evidence suggests that changes in cardiomyocytes' phospholipid profiles are associated with an increased occurrence of cardiovascular diseases, but the underlying mechanisms are still poorly understood. This review aims to provide a comprehensive overview of the significant impact of PLC on the cardiovascular system, encompassing both physiological and pathological conditions. Specifically, it focuses on the relevance of PLCβ isoforms as potential cardiac biomarkers, due to their implications for pathological disorders, such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial ischemia/reperfusion injury. Gaining a deeper understanding of the mechanisms underlying PLCβ activation and regulation is crucial for unraveling the complex signaling networks involved in healthy and diseased myocardium. Ultimately, this knowledge holds significant promise for advancing the development of potential therapeutic strategies that can effectively target and address cardiac disorders by focusing on the PLCβ subfamily.
Topics: Animals; Humans; Isoenzymes; Phospholipase C beta; Heart Diseases; Myocytes, Cardiac; Biomarkers; Mammals
PubMed: 37685903
DOI: 10.3390/ijms241713096 -
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 -
Food Science & Nutrition Oct 2023(Wangenh.) K. Koch, nuts are a renowned health food. However, there are many cultivars of this nut tree, and their mature kernel lipid composition has not been...
(Wangenh.) K. Koch, nuts are a renowned health food. However, there are many cultivars of this nut tree, and their mature kernel lipid composition has not been thoroughly studied. Therefore, we used liquid chromatography-mass spectrometry (LC-MS) to analyze the lipid composition of mature nuts of five cultivars In the mature kernels of all cultivars, there were 58 lipid types which were mainly composed of glycerolipids (c. 65%) and phospholipids (>30%). Triacylglycerol (TG) accounted for the largest proportion of mature nuts of all cultivars, exceeding 50%; and diacylglycerol (DG), ceramide (Cer), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) were also relatively high. Additionally, nuts contain fatty acids, mainly oleic, linoleic, and linolenic acids. Our research provides a new perspective for the processing and utilization of plant and edible oils, and for the use of kernels in the development of medicine and food science.
PubMed: 37823132
DOI: 10.1002/fsn3.3572 -
Biomedicines Jul 2023Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML)...
Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including , and , without a precise correlation with specific AML subtypes. In the TGCA database, high expression negatively correlates with survival, while high expression is associated with a more favorable prognosis. and also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the and isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability.
PubMed: 37509516
DOI: 10.3390/biomedicines11071877 -
Proceedings of the National Academy of... Aug 2023Here, we introduce the full functional reconstitution of genetically validated core protein machinery (SNAREs, Munc13, Munc18, Synaptotagmin, and Complexin) for synaptic...
Here, we introduce the full functional reconstitution of genetically validated core protein machinery (SNAREs, Munc13, Munc18, Synaptotagmin, and Complexin) for synaptic vesicle priming and release in a geometry that enables detailed characterization of the fate of docked vesicles both before and after release is triggered with Ca. Using this setup, we identify new roles for diacylglycerol (DAG) in regulating vesicle priming and Ca-triggered release involving the SNARE assembly chaperone Munc13. We find that low concentrations of DAG profoundly accelerate the rate of Ca-dependent release, and high concentrations reduce clamping and permit extensive spontaneous release. As expected, DAG also increases the number of docked, release-ready vesicles. Dynamic single-molecule imaging of Complexin binding to release-ready vesicles directly establishes that DAG accelerates the rate of SNAREpin assembly mediated by chaperones, Munc13 and Munc18. The selective effects of physiologically validated mutations confirmed that the Munc18-Syntaxin-VAMP2 "template" complex is a functional intermediate in the production of primed, release-ready vesicles, which requires the coordinated action of Munc13 and Munc18.
Topics: Humans; Diglycerides; Synaptic Vesicles; Exocytosis; Synaptic Transmission; Synaptotagmins; Blister
PubMed: 37590407
DOI: 10.1073/pnas.2309516120 -
Scientific Reports Oct 2023The coronavirus disease 2019 (COVID-19), which affects multiple organs, is causing an unprecedented global public health crisis. Most COVID-19 patients recover gradually...
The coronavirus disease 2019 (COVID-19), which affects multiple organs, is causing an unprecedented global public health crisis. Most COVID-19 patients recover gradually upon appropriate interventions. Viruses were reported to utilize the small extracellular vesicles (sEVs), containing a cell-specific cargo of proteins, lipids, and nucleic acids, to escape the attack from the host's immune system. This study aimed to examine the sEVs lipid profile of plasma of recovered COVID-19 patients (RCs). Plasma sEVs were separated from 83 RCs 3 months after discharge without underlying diseases, including 18 recovered asymptomatic patients (RAs), 32 recovered moderate patients (RMs), and 33 recovered severe and critical patients (RSs), and 19 healthy controls (HCs) by Total Exosome Isolation Kit. Lipids were extracted from sEVs and then subjected to targeted liquid chromatography-mass spectrometry. The size, concentration, and distribution of sEVs did not differ in RCs and HCs as validated by transmission electron microscopy, nanoparticle tracking analysis, and immunoblot analysis. Fifteen subclasses of 508 lipids were detected in plasma sEVs from HCs, RAs, RMs, and RSs, such as phosphatidylcholines (PCs) and diacylglycerols (DAGs), etc. Total lipid intensity displayed downregulation in RCs compared with HCs. The relative abundance of DAGs gradually dropped, whereas PCs, lysophosphatidylcholines, and sphingomyelins were higher in RCs relative to HCs, especially in RSs. 88 lipids out of 241 in sEVs of RCs were significantly different and a conspicuous increase was revealed with disease status. The sEVs lipids alternations were found to be significantly correlated with the clinical indices in RCs and HCs, suggesting that the impact of COVID-19 on lipid metabolism lingered for a long time. The lipid abnormalities bore an intimate link with glycerophospholipid metabolism and glycosylphosphatidylinositol anchor biosynthesis. Furthermore, the lipidomic analysis showed that RCs were at higher risk of developing diabetes and sustaining hepatic impairment. The abnormality of immunomodulation in RCs might still exist. The study may offer new insights into the mechanism of organ dysfunction and help identify novel therapeutic targets in the RCs.
Topics: Humans; Lipid Metabolism; COVID-19; Extracellular Vesicles; Exosomes; Diglycerides
PubMed: 37789017
DOI: 10.1038/s41598-023-43189-5 -
Journal of Lipid Research Feb 2024HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in...
HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome.
Topics: Male; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proteome; Diglycerides; Lipidomics; Ceramides; Cholesterol; Hypertriglyceridemia; Hyperlipidemias; Cholesterol, HDL; Triglycerides; Phosphatidylcholines; Quinolines
PubMed: 38160756
DOI: 10.1016/j.jlr.2023.100494 -
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 -
Cells Sep 2023Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown....
Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A (iPLA) releases lysophospholipids such as LPA or arachidonic acid (AA) and that inhibiting PRDX6 iPLA activity impairs sperm cell viability. The exogenous addition of LPA bypassed the inhibition of PRDX6 iPLA activity and maintained the active phosphoinositide 3-kinase (PI3K)/AKT pathway. Here, we aimed to study PI3K/AKT pathway regulation via LPA signalling and protein kinases in maintaining sperm viability. The localization of LPARs in human spermatozoa was determined using immunocytochemistry, and P-PI3K and P-AKT substrate phosphorylations via immunoblotting. Sperm viability was determined using the hypo-osmotic swelling test. LPAR1, 3, 5 and 6 were located on the sperm plasma membrane. The inhibition of LPAR1-3 with Ki16425 promoted the impairment of sperm viability and decreased the phosphorylation of PI3K AKT substrates. Inhibitors of PKC, receptor-type PTK and PLC impaired sperm viability and the PI3K/AKT pathway. Adding 1-oleoyl-2-acetyl-snglycerol (OAG), a cell-permeable analog of diacylglycerol (DAG), prevented the loss of sperm viability and maintained the phosphorylation of PI3K. In conclusion, human sperm viability is supported by LPAR signalling and regulated by PLC, PKC and RT-PTK by maintaining phosphorylation levels of PI3K and AKT substrates.
Topics: Humans; Male; Lysophospholipids; Peroxiredoxin VI; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Semen
PubMed: 37681929
DOI: 10.3390/cells12172196 -
Arteriosclerosis, Thrombosis, and... Mar 2024Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into...
BACKGROUND
Oxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a).
METHODS
Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNA sequencing, ELISA, Western blot, and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions.
RESULTS
Compared with healthy individuals with low/normal Lp(a) levels (median, 7 mg/dL [18 nmol/L]; n=13), individuals with elevated Lp(a) levels (median, 87 mg/dL [218 nmol/L]; n=12) demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68IL-18TLR4 (toll-like receptor) TREM2 (triggering receptor expressed on myeloid cells) resident macrophages and CD68CASP1 (caspase) IL-1BSELL (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]).
CONCLUSIONS
Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent.
Topics: Humans; Diglycerides; Inflammasomes; Inflammation; Interleukin-1beta; Interleukin-6; Lipoprotein(a); Lysophospholipids; Monocytes; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 38269588
DOI: 10.1161/ATVBAHA.123.319937