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PROVIDER: PRJEB57553 | ENA |
REPOSITORIES: ENA
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Project description:We identified that HK2 facilitate the maintenance and self-renewal of liver cancer stem cells (CSCs). Moreover, HK2 exerts its function by enhancing the accumulation of acetyl-CoA and epigenetically activating the transcription of acyl-CoA synthetase long chain family member 4 (ACSL4), leading to an increase in fatty acid β-oxidation (FAO) activity.
2022-05-06 | GSE184798 | GEO
Project description:Floodings already have a nearly 60% share in the worldwide damage to crops provoked by natural disasters. Climate change will cause plants to be even more frequently exposed to oxygen limiting conditions (hypoxia) in the near future due to heavy precipitation and concomitant waterlogging or flooding events in large areas of the world. Although the homeostatic regulation of adaptive responses to low oxygen stress in plants is well described, it remained unknown by which initial trigger the molecular response to low-oxygen stress is activated. Here, we show that a hypoxia-induced decline of the ATP level of the cell reduces LONG-CHAIN ACYL-COA SYNTHETASE (LACS) activity, which leads to a shift in the composition of the acyl-CoA pool. High oleoyl-CoA levels release the transcription factor RELATED TO APETALA 2.12 (RAP2.12) from its interaction partner ACYL-COA BINDING PROTEIN (ACBP) at the plasma membrane to induce low oxygen-specific gene expression. We show that different acyl-CoAs provoke unique molecular responses revealing a novel role as cellular signalling component also in plants. In terms of hypoxia signalling, dynamic acyl-CoA levels integrate the cellular energy status into the oxygen signalling cascade with ACBP and RAP2.12 being the central hub. The conserved nature of the ACBP:RAP2.12 module in crops and the novel mechanistic understanding of how low-oxygen stress responses are initiated by oleoyl-CoA in plants provide useful leads for enhancing future food security.
2018-04-30 | GSE97186 | GEO
Project description:TNF-alpha has a number of pro-atherogenic effects in macrovascular endothelial cells, including induction of leukocyte adhesion molecules and chemokines. We investigated the role of acyl-CoA synthetase 3 (ACSL3) in the response of cultured human macrovascular endothelial cells to TNF-alpha. TNF-alpha induced ACSL3 both in human umbilical vein endothelial cells (HUVECs) and in human coronary artery endothelial cells (HCAECs). RNA sequencing demonstrated that knockdown of ACSL3 had no marked effects on the TNF-alpha transcriptome in HCAECs. Instead, ACSL3 was required for TNF-alpha-induced lipid droplet formation from fatty acids.
2019-11-23 | GSE134489 | GEO
Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.
2021-02-08 | GSE162069 | GEO
Project description:The ER-resident prote in fat-inducing transcript 2 (FIT2) catalyzes acyl-CoA cleavage in vitro, and in cells is required for endoplasmic reticulum (ER)homeostasis and normal lipid storage. The gene encoding FIT2 is essential for viability of mice and worms. Whether FIT2 acts as anacyl-CoA diphosphatase in vivo and how this activity affects liver, where the protein was discovered,is unknown. Here, we report that hepatocyte-specific Fitm2 knockout (FIT2-LKO) mice exhibited elevated acyl-CoA levels, ER stress, and signs of liver injury. FIT2-LKO mice had increased triglyceride (TG) content in liver when fed a chow diet, compared with control littermates due in part to impaired secretion of TG-rich lipoproteins and reduced capacity for fatty acid oxidation. Challenging FIT2-LKO mice with a high-fat diet to increase FIT2 acyl-CoA substrates worsened hepatic ER stress and liver injury, yet unexpectedly reversed the steatosis phenotype, similar to what is observed in FIT2-deficient cells loaded with fatty acids. Our findings show that FIT2 acts as anacyl-CoA diphosphatase in vivo and is crucial for normal hepatocyte function and ER homeostasis in murine liver
2023-05-10 | PXD033884 | Pride
Project description:Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity.
2023-05-04 | GSE202279 | GEO
Project description:Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity.
2023-05-04 | GSE202280 | GEO
Project description:Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution.
2017-06-01 | GSE86384 | GEO
Project description:Mutton has recently been identified to be a consumer favorite, and intermuscular fat is the key factor in determining meat tenderness. Long-chain acyl-CoA synthetase 1 (ACSL1) is a vital subtype of the ACSL family that is involved in the synthesis of lipids from acyl-CoA and the oxidation of fatty acids. The amplification of the ACSL1 gene using rapid amplification of cDNA ends revealed that the alternative polyadenylation (APA) results in two transcripts of the ACSL1 gene. Exon 18 had premature termination, resulting in a shorter CDS region. In this study, the existence of two transcripts of varying lengths translated normally and designated ACSL1-a and ACSL1-b was confirmed. Overexpression of ACSL1-a can promote the synthesis of an intracellular diglyceride, while ACSL1-b can promote triglyceride synthesis. The transfection of ACSL1 shRNA knocks down both the transcripts, the triglyceride content was significantly reduced after differentiation and induction; and lipidome sequencing results exhibited a significant decrease in 14-22 carbon triglyceride metabolites. The results of the present study indicated that the ACSL1 gene played a crucial role in the synthesis of triglycerides. Furthermore, the two transcripts involved in various interactions in the triglyceride synthesis process may be the topic of interest for future research and provide a more theoretical basis for sheep breeding.
2023-02-06 | MTBLS5808 | MetaboLights
Project description:Overexpression of Long Chain Acyl CoA Synthetase 1 effects on Lipid Metabolism in Sheep adipocytes
| PRJNA597228 | ENA