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Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation [II]

ABSTRACT: To test the role of FAO in epithelium differentiation, we assessed genome-wide transcriptional changes in Cpt1a+/- and Cpt1a-/- primary mouse tracheal epithelial cell (mTEC) cultures analysed at the end of the expansion phase (ALI day 0) or at day 5 and 7 post air-exposure by RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE209684 | GEO | 2023/01/31

REPOSITORIES: GEO

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Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation [I]

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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

ROLE OF FATTY ACID ß-OXIDATION IN LYMPHANGIOGENESIS

Project description:Lymphatic vessels are involved in fluid drainage and are critical for health. To date, only genetic signaling pathways have been implicated in lymphatic development, and a role for metabolism has not been described. Here, we report that transcription factor Prox1 increases fatty acid ß-oxidation (FAO) through upregulation of CPT1a, a rate-controlling step of FAO. Lymphatic endothelial cells (LECs) oxidize fatty acids to proliferate and migrate. By providing acetyl-CoA, FAO is also critical for the maintenance of differentiated LECs through the regulation of histone acetylation of key lymphangiogenic genes. Loss of CPT1a in LEC precursors causes lymphatic defects in vivo, while restoration of acetyl-CoA by supplementing acetate to replenish cellular acetyl-CoA levels rescues this process.

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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.

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

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.

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Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

Project description:Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

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Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-31 | GSE209686 | GEO

FDXR Drives Primary and Endocrine Resistant Tumor Cell Growth in ER+ Breast Cancer via CPT1A-Mediated Fatty Acid Oxidation

Project description:The majority of breast cancers (BCs) harboring estrogen receptor (ER) have shown endocrine resistance. Our previous study has demonstrated that ferredoxin reductase (FDXR) promotes mitochondrial function and ER+ breast tumorigenesis. Here, integrative analyses of targeted metabolomics assay and gene expression profiling show that FDXR potentiates fatty acid oxidation (FAO) through positive regulation of carnitine palmitoyltransferase 1A (CPT1A) expression. Treatment with ER antagonist (tamoxifen) or degrader (fulvestrant) leads to increased expression of FDXR and CPT1A. In line with this finding, we find that FDXR-CPT1A-FAO axis is required for primary and endocrine resistant breast cancer cell growth. Therapeutically,combining endocrine therapy with FAO inhibitor synergistically reduces primary and endocrine resistant breast cancer cell growth, thus providing a potential combinatory treatment for ER+ breast cancer. We used microarrays to be able to elucidate to some extent the gene regulatory mechanisms of FDXR regulating breast cancer metabolism.

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2015-01-28 | PXD001186 | Pride

RNAseq of MTEC (mouse tracheal epithelial cells) during 0, 4 and 7 days in ALI

Project description:We want to observe the dynamics of MTEC differentiation by looking at the gene expression differences at two points: ALI (Air-Liquid Interface) 4 days, and ALI 7 days.

2020-03-16 | E-MTAB-8852 | biostudies-arrayexpress

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