Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition

Glatzel, Daniel; Koeberle, Andreas; Pein, Helmut; Löser, Konstantin; Stark, Anna; Keksel, Nelli; Werz, Oliver; Müller, Rolf; Bischoff, Iris; Fürst, Robert

doi:10.1194/jlr.m080101

Cited by 46 publications

(48 citation statements)

References 50 publications

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“…Additionally, we were unable to detect a change in inhibitory phosphorylation of ACC1 by AMPK at serine 79, so there is not increased inhibition of ACC1 with TMG treatment. Of note, lipidomics analysis of endothelial cells treated with soraphen A, a potent inhibitor of ACC1, resulted in opposite effects of what we observed (Glatzel et al, 2017). With inhibition of ACC1, polyunsaturated fatty acids (PUFA) increased, whereas we observed a significant decrease in PUFAs in our T cell model.…”

Section: Discussioncontrasting

confidence: 54%

Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Lipid Microenvironment

Machacek

2018

Preprint

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SUMMARYChronic, low-grade inflammation increases the risk of atherosclerosis, cancer, and autoimmunity in diseases like obesity and diabetes. Here, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine) are present in naïve CD4+ T cells from a diet-induced obesity murine model, and elevation in O-GlcNAc leads to increased pro-inflammatory IL-17A production. Importantly, CD4+ T helper 17 (Th17) cells, which secrete IL-17A, are increased in obesity and contribute to the inflammatory milieu. We found increased binding of the Th17 master transcription factor, RORγt, at the IL-17 locus and significant alterations in the lipid microenvironment, leading to increased ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl CoA carboxylase 1 (ACC1), is necessary for production of these RORγt activating ligands and is O-GlcNAcylated. Thus, we have identified O-GlcNAc as a critical link between excess nutrients and pathological inflammation.

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Section: Discussioncontrasting

confidence: 54%

Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Lipid Microenvironment

Machacek

2018

Preprint

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“…TAGs were extracted using a mixture of PBS pH 7.4, methanol, chloroform, and saline (14:34:35: 17), separated on an AcquityTM UPLC BEH C8 column (1.7 μm, 2.1 × 100 mm, Waters, Milford, MA) using an AcquityTM Ultraperformance LC system (Waters) and detected by a QTRAP 5500 mass spectrometer (Sciex, Darmstadt, Germany) equipped with an electrospray ionization source as described [19]. Acyl-CoAs were extracted with methanol/water (70/30), separated on an AcquityTM UPLC BEH C18 column (1.7 μM, 2.1 × 50 mm), and analyzed in the positive ion mode based on the neutral loss of 2′-phospho-ADP ([M + H-507]+) as previously reported for malonyl-CoA [20]. 1,2-Dimyristoyl-sn-glycero-3-phosphatidylcholine and [13C3]-malonyl-CoA were used as internal standards for TAGs and acyl-CoAs, respectively.…”

Section: Methodsmentioning

confidence: 99%

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

et al. 2019

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Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors. Graphical Abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0399-2) contains supplementary material, which is available to authorized users.

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“…Extraction and analysis of acyl-CoAs was performed using [ 13 C 3 ]-malonyl-CoA as internal standard. 18 In brief, acyl-CoAs were separated on an Acquity UPLC BEH C18 column (1.7 µM, 2.1 × 50 mm) and detected based on the neutral loss of 2′-phospho-ADP ([M + H-507] + ) in the positive ion mode using the UPLCcoupled tandem ESI-MS system described above. Mass spectra were processed using Analyst 1.6 (Sciex, Darmstadt, Germany).…”

Section: Analysis Of Fatty Acids Phospholipids and Acyl-coasmentioning

confidence: 99%

Metabolic implication of tigecycline as an efficacious second‐line treatment for sorafenib‐resistant hepatocellular carcinoma

et al. 2020

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Sorafenib represents the current standard of care for patients with advanced‐stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy‐limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation‐inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA‐encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second‐line therapeutic approach for advanced‐stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.

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Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition

Cited by 46 publications

References 50 publications

Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Lipid Microenvironment

Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Lipid Microenvironment

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

Metabolic implication of tigecycline as an efficacious second‐line treatment for sorafenib‐resistant hepatocellular carcinoma

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