Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide analysis of differential gene expression of contact-inhibited versus proliferating endothelial cells

ABSTRACT: Brief summary: Analysis of gene expression in endothelial cells upon contact-inhibition. With this experiments we aimed to identify genes that are associated with the induction of cellular quiescence. Abstract from the associated publication: In contrast to the growing insight in the metabolic reprogramming underlying the angiogenic switch, little is known about the metabolic changes accompanying the quiescence of endothelial cells (ECs). Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple diseases. Here, we report that QECs are not hypometabolic, but upregulate fatty acid β-oxidation (FAO), not for energy or biomass production, but for redox homeostasis. Hence, inhibition of CPT1a, a rate-controlling step of fatty acid breakdown, promotes a pro-thrombotic and pro-inflammatory signature of QECs by increasing oxidative stress. EC-specific genetic loss similarly elevates oxidative stress in vivo. Compared to proliferating ECs (PECs), QECs switch on a broad “vasculoprotective” metabolic program, involving (i) NAPDH production by the oxidative pentose phosphate pathway (oxPPP) and nicotinamide nucleotide transhydrogenase (NNT), and (ii) prostacyclin synthesis. Molecularly, pro-quiescent Notch signaling elevates FAO by upregulating CPT1a gene transcription. Thus, QECs switch on vasculoprotective metabolic reactions to ensure vascular health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89174 | GEO | 2018/10/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis

Project description:Little is known about metabolic changes accompanying endothelial cell (EC) quiescence. Nonetheless, when dysfunctional, quiescent ECs (QECs) contribute to multiple cardiovascular diseases. ECs need fatty acid β-oxidation (FAO) for proliferation. Surprisingly, we now report that QECs are not hypo-metabolic, but upregulate FAO >3-fold higher than proliferating ECs (PECs), not to support biomass or energy production, but to sustain the TCA cycle for redox homeostasis through NADPH production. Hence, inhibition of FAO-controlling CPT1A promotes EC dysfunction (anti-fibrinolysis, leukocyte infiltration, barrier disruption) by increasing oxidative stress in CPT1AΔEC mice with endothelial CPT1A loss. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-CoA) induces vasculoprotection against oxidative stress and EC dysfunction in CPT1AΔEC mice, possibly creating therapeutic opportunities. Thus, ECs use FAO for vasculoprotection against their high oxygen (oxidative stress-prone) milieu, and for different metabolic purposes dependent on their proliferation versus quiescence status.

2018-09-12 | E-MTAB-6595 | biostudies-arrayexpress

A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell quiescence

Project description:Adult hippocampal neurogenesis is important for certain forms of cognition and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. However, how this balance is regulated remains poorly understood. Here we show that the rate of fatty acid oxidation (FAO) defines quiescence vs. proliferation in NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, experimental manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.

2019-11-15 | PXD005598 | Pride

A role for CPT1A to prevent blood vessel permeability revealed by in depth proteomics

Project description:Endothelial cells (ECs) line the inner wall of blood vessels and maintain vascular stability. Vascular stability alteration is a hallmark of pathologies such as cancer and thrombosis. A role for fatty acid oxidation (FAO) in this process is unknown. Integrating MS-proteomics and metabolic modeling revealed that FAO increases when ECs cultured on matrigel are assembled into a fully formed network. Inhibition of CPT1A in ECs, a limiting enzyme in FAO, results in disruption of this network. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which can be restored replenishing the tricarboxylic acid cycle (TCAc). Phosphoproteomic changes upon acute CPT1A inhibition evoked those triggered by thrombin, a potent inducer of EC permeability through calcium signaling. Indeed, CPT1A inhibition increased EC permeability and vascular leakage, which were restored replenishing the TCAc or, partially, inhibiting calcium influx. Our study shows the possibility of altering FAO to interfere with ECs in diseases.

2015-01-28 | PXD001186 | Pride

HFD activated FAO mediates intestinal stemness and tumorgenicity I

Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.

2021-06-01 | GSE151045 | GEO

HFD activated FAO mediates intestinal stemness and tumorgenicity II

2021-06-01 | GSE151046 | GEO

High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

2021-06-01 | GSE167996 | GEO

Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy

Project description:Metabolic reprogramming is a hallmark of tumorigenesis and includes alterations in glucose and fatty acid metabolism. In this study, we investigated the role of Carnitine palmitoyl transferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), in the induction of HER2+ (Human Epidermal growth factor 2, ErbB2) breast cancer. Using an ErbB2+ genetically engineered mouse models, we found that ablation of CPT1A delayed tumor onset and reduced tumor growth, angiogenesis, and metastatic capacity. CPT1A-deficient ErbB2+ cells exhibited impaired mitochondrial function, leading to a reliance on the tricarboxylic acid cycle to reduce NAD+/FAD for energy production. Consequently, loss of CPT1A resulted in glucose dependency and an inability to metabolize fats. CPT1A-deficient ErbB2+ tumor cells exhibited increased oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (NRF2) activity. Inhibiting NRF2 or silencing its expression reduced proliferation and glucose consumption in CPT1A-deficient cells. In pre-clinical models of ErbB2+ breast cancer, combining a ketogenic diet with an anti-ErbB2 monoclonal antibody in the context of CPT1A deficiency significantly reduced tumor growth and increased survival. Furthermore, combining the ketogenic diet with CPT1A ablation suppressed tumor growth, enhanced apoptosis, and reduced lung metastasis. Additionally, using an immunocompetent model, we provide evidence that CPT1A inhibition attenuated tumor growth and proliferation by promoting an antitumor immune microenvironment that enhanced the efficacy of ErbB2 targeted therapy. These findings provide insight into the metabolic rewiring in HER2+ breast cancer and highlight the potential of targeting fatty acid oxidation and employing metabolic interventions as a combination therapy strategy for HER2+ breast cancer patients, including those resistant to standard treatment regimes.

2024-07-08 | GSE254622 | GEO

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Project description:Adult neural stem cells are largely quiescent, and require transcriptional reprogramming to re-enter the cell cycle before neurogenesis. However, mechanisms underlying the transcriptional overhaul during NSC activation remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Interestingly, accessible chromatin states specific to activation or quiescence are active enhancers bound by pro-neurogenic and quiescence factors, ASCL1 and NFI. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to downregulation of gene expression and associated with pro-quiescence factors, revealing a novel mechanism that may preserve quiescence re-entry. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation.

2021-11-17 | GSE161578 | GEO

A single metabolite which modulates lipid metabolism alters hematopoietic stem/progenitor cell behavior and promotes lymphoid reconstitution

Project description:Fatty acid beta-oxidation (FAO), the breakdown of lipids, is a metabolic pathway used by various stem cells. FAO levels are generally high during quiescence and downregulated with proliferation. The endogenous metabolite malonyl-CoA modulates lipid metabolism as a reversible FAO inhibitor and as a substrate for de novo lipogenesis. Here we assessed whether malonyl-CoA can be exploited to steer the behavior of hematopoietic stem/progenitor cells (HSPCs), quiescent stem cells of clinical relevance. Treatment of mouse HSPCs in vitro with malonyl-CoA increases HSPC numbers compared to non-treated controls and ameliorates blood reconstitution capacity when transplanted in vivo, mainly through enhanced lymphoid reconstitution. Similarly, human HSPC numbers also increase upon malonyl-CoA treatment in vitro. These data corroborate that lipid metabolism can be targeted to direct cell fate and stem cell proliferation. Physiological modulation of metabolic pathways, rather than genetic or pharmacological inhibition, provides unique perspectives for stem cell manipulations in health and disease.

2020-08-25 | GSE153201 | GEO

Graded regulation of cellular quiescence depth between proliferation and senescence by a lysosomal dimmer switch

Project description:The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is however not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly upregulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Lastly, we found that a gene expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.

2019-10-11 | GSE124109 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data