Saccharomyces cerevisiae
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA305165 | ENA |
REPOSITORIES: ENA
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Project description:Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes including yeast. PC has been assigned a multitude of functions in addition to that of building block of the lipid bilayer. Here we show that PC is evolvable essential in yeast by isolating suppressor mutants devoid of PC that exhibit robust growth. The requirement for PC is suppressed by monosomy of chromosome XV, or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis differently, both decrease Acc1 activity thereby reducing the average acyl chain length. Accordingly, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, up-regulation of lipid synthesis is instrumental to accomplish feed-back inhibition of Acc1 by acyl-CoA produced by the fatty acid synthase (FAS). The results show that yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS, and indicate that PC evolved by benefitting the maintenance of membrane fluidity.
2021-08-04 | GSE75725 | GEO
Project description:Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.
2024-07-16 | GSE235302 | GEO
Project description:Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.
2024-07-16 | GSE234884 | GEO
Project description:Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in need of new more specific therapeutic regimen. The drivers of malignancy in this disease are CD4+ follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option. Methods: To reveal the prominent metabolic pathways used by the AITL lymphoma cells, leveraged on our previously established AITL mouse model by crossing metabolomic and proteomic data of murine AITL cells. We confirmed these results using AITL patient and healthy T cell expression data. Results: Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, respectively, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with the fatty acid oxydation inhibitor, etomoxir, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chok confirmed the importance of the phosphatidylcholine production pathway in the neoplastic CD4+ T cells, since it irradicated almost all the mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1high neoplastic cells. Conclusion: Our results suggest that interfering with the choline metabolism in AITL might represent a new therapeutic strategy for these patients.
2024-04-04 | PXD046786 | Pride
Project description:Mesenchymal stem/stromal cells (MSCs) with immunosuppressive properties are increasingly used in advanced cellular therapies. Since the clinical use of hMSCs demands sequential cell expansions, we studied the effect of cell doublings on the phospholipid profile as well as functionality of human bone marrow mesenchymal stem cells (hBMSCs). In addition to the structural role of phospholipids in cell membranes, they provide precursors for eicosanoids and other signalling lipids modulating cellular functions. The hBMSCs, harvested from young adult and old donors (n=5 for both), showed clear compositional changes during cultivation, seen at the level of lipid classes, lipid species and acyl chains. As the main finding at the lipid class level, the ratio of phosphatidylinositol to phosphatidylserine was increased towards the late passage samples. In the species profiles, arachidonic acid (AA) containing species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) clearly accumulated, while the species containing monounsaturated fatty acids decreased. This was related with an increase of AA, a major n-6 polyunsaturated fatty acid (n-6PUFA), in the total fatty acid pool of the cells, which happened at the expense of n-3PUFAs, especially docosahexenoic acid (DHA). Using hBMSCs from four of the young adult donors and four of the old donors, we found that gene expression of several enzymes involved in fatty acid metabolism (such as FADS1, FADS2 and SCD) was altered. The expression of genes related to the regulation of cell cycle, senescence and immunomodulation were altered. Our findings suggest that multistep expansion of hBMSCs alters their fatty acid metabolism and membrane phospholipid composition, which affects lipid signalling and eventually the immune function of the cells. Cultured undifferentiated bone marrow-derived MSCs from old and young donors. Biological replicates: 4 old donors and 4 young donors, passages 4 and 8 from each.
2013-04-05 | E-GEOD-39035 | biostudies-arrayexpress
Project description:Lipid remodeling is crucial for plant responses to abiotic stress and metabolic disturbances. A key aspect of this process involves the modification of phosphatidylcholine (PC) acyl chains by lysophosphatidylcholine: acyl-CoA acyltransferases (LPCATs). To understand their role in lipid homeostasis, we studied the trigalactosyldiacylglycerol1 (tgd1) mutant, which exhibits significant increases in fatty acid synthesis and flux through PC due to disrupted inter-organelle lipid trafficking. We discovered that the elevated fatty acid synthesis in tgd1 is due to the posttranslational activation of plastidic acetyl-coenzyme A carboxylase (ACCase). Global transcriptomic profiling revealed 62 significantly upregulated genes in tgd1, with 27 (44%) involved in RNA and DNA modifications, suggesting a role for posttranscriptional mechanisms in adapting to lipid trafficking disruptions. Additionally, transcript levels of LPCATs and several genes regulating ACCase were moderately increased in tgd1. Genetic analysis showed that knocking out LPCAT1 and LPCAT2 was lethal in the tgd1 background. Furthermore, plants homozygous for lpcat2 and heterozygous for lpcat1 in the tgd1 background displayed reduced levels of PC and TAG, along with altered fatty acid compositions. Our findings provide mechanistic insights into fatty acid synthesis regulation and highlight the critical role of LPCATs in maintaining cellular lipid homeostasis when fatty acid production exceeds the cellular demand for membrane lipid synthesis.
2024-09-16 | PXD054661 | Pride
Project description:Phosphatidylcholine is a membrane lipid. To determine its role in the intestine, we deleted the gene that produces this lipid specificallly in intestinal epithelial cells and conducted expression analysis. We used microarray analysis to determine changes in gene expression that occur in the absence of intestinal phosphatidylcholine synthesis.
2021-02-04 | GSE129776 | GEO
Project description:Phosphatidylcholine is a membrane lipid. To determine its role in the intestine, we deleted the gene that produces this lipid specificallly in intestinal epithelial cells and conducted expression analysis. We used microarray analysis to determine changes in gene expression that occur in the absence of intestinal phosphatidylcholine synthesis.
2021-02-04 | GSE110474 | GEO
Project description:Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio circa 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) - predicted by molecular dynamics simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-beta secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimer's disease.
2025-07-25 | GSE299277 | GEO
Project description:Mesenchymal stem/stromal cells (MSCs) with immunosuppressive properties are increasingly used in advanced cellular therapies. Since the clinical use of hMSCs demands sequential cell expansions, we studied the effect of cell doublings on the phospholipid profile as well as functionality of human bone marrow mesenchymal stem cells (hBMSCs). In addition to the structural role of phospholipids in cell membranes, they provide precursors for eicosanoids and other signalling lipids modulating cellular functions. The hBMSCs, harvested from young adult and old donors (n=5 for both), showed clear compositional changes during cultivation, seen at the level of lipid classes, lipid species and acyl chains. As the main finding at the lipid class level, the ratio of phosphatidylinositol to phosphatidylserine was increased towards the late passage samples. In the species profiles, arachidonic acid (AA) containing species of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) clearly accumulated, while the species containing monounsaturated fatty acids decreased. This was related with an increase of AA, a major n-6 polyunsaturated fatty acid (n-6PUFA), in the total fatty acid pool of the cells, which happened at the expense of n-3PUFAs, especially docosahexenoic acid (DHA). Using hBMSCs from four of the young adult donors and four of the old donors, we found that gene expression of several enzymes involved in fatty acid metabolism (such as FADS1, FADS2 and SCD) was altered. The expression of genes related to the regulation of cell cycle, senescence and immunomodulation were altered. Our findings suggest that multistep expansion of hBMSCs alters their fatty acid metabolism and membrane phospholipid composition, which affects lipid signalling and eventually the immune function of the cells.
2013-04-05 | GSE39035 | GEO