Fatty acid oxidation downregulation in alveolar epithelial 2 cells promotes acute lung injury in obesity
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ABSTRACT:
PROVIDER: PRJNA1102267 | ENA |
REPOSITORIES: ENA
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Project description:Obesity is associated with increased risk for acute respiratory distress syndrome (ARDS). High fat diet induced obesity was linked to increased lung injury and bronchoalveolar lavage fluid (BALF) free fatty acids in a hyperoxic model of ARDS. In this study, we show significant transcriptional downregulation of fatty acid oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2) of obese compared to lean mice after hyperoxia. AEC2 from obese mice exhibited increased intracellular lipids, more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared to lean mice. FAO downregulation in AEC2 through a genetic mouse model targeting carnitine palmitoyltransferase 1A (Cpt1aloxp/loxpSftpcCreERT2+/– mice) resulted in further increased BALF fatty acids and lung injury in obese mice. High fat diet was associated with markers of impaired alveolar epithelial regeneration after hyperoxia, which include reduced surfactant AEC2 lineage markers, as well as reduced surfactant related phospholipids in hyperoxic AEC2, and increased BALF surface tension. In a reanalysis of a human molecular single-cell lung atlas of COVID19 ARDS, significant downregulation of the FAO signature in AEC2 compared to controls was observed only in ARDS patients with BMI >30, and not those with BMI <30.
2025-04-18 | GSE264369 | GEO
Project description:It has been found that fat oxidation is reduced in the skeletal muscle of obese humans. This study aims to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals. Information gathered will help in understanding how obesity contributes to cardiovascular disease via insulin resistance. Keywords: other
2003-07-16 | GSE474 | GEO
Project description:The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival or death, the metabolic response to DNA damage remains largely obscure. Here, we show that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through PPARα, accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, we find that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.
2024-03-20 | GSE208632 | GEO
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the steady-state model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000505
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000505 | BioModels
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (time-course model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the time-course model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000506
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000506 | BioModels
Project description:Alveolar epithelial cells mitigate neutrophilic inflammation in acute lung injury through regulating mitochondrial fatty acid oxidation
| PRJNA930707 | ENA
Project description:Induction of fatty acid oxidation underlies DNA damage-induced cell death and ameliorates obesity-driven chemoresistance
| PRJNA860379 | ENA
Project description:Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation
2023-01-31 | GSE218663 | GEO
Project description:Metabolic remodeling is one of the earliest events that occur during the early differentiation of embryonic stem cells (ESCs), but how these metabolic changes are regulated and participate in the cell differentiation is still largely undissected. Here, we define the fatty acid metabolism as a key player in definitive endoderm (DE) differentiation from human ESCs. During DE differentiation, lipogenesis is decreased while fatty acid β oxidation is enhanced. This dynamic is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase (ACC), which is mediated by AMP-activated protein kinase (AMPK) and inhibits the de novo fatty acid synthesis. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist, significantly promotes the human endoderm differentiation, while blockade of the fatty acid oxidation by genetic manipulation or chemical antagonists impairs the differentiation. The de novo fatty acid synthesis inhibition and fatty acid β oxidation maintaining contribute to the accumulation of cellular acetyl-CoA, which is the essential substrate for protein acetylation. Further study reveals that SMAD3 acetylation and the subsequent subcellular localization exhibit significant change upon interfering fatty acid metabolism. Mechanistically, the accumulation of cellular acetyl-CoA guarantees the acetylation of key transcription factor SMAD3, which further causes the nuclear localization and activation of SMAD signaling pathway to promote DE differentiation. Thus, our current study reveals a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role of fatty acid metabolism in regulating human early endoderm differentiation.
2023-07-02 | GSE218319 | GEO
Project description:Dietary polyunsaturated fatty acids (PUFA) act as potent natural hypolipidemics and are linked to many health benefits in humans and in animal models. Mice fed long-term a high fat diet, in which medium-chain alpha linoleic acid (ALA) was partially replaced by long-chain docosahexaenoic (DHA) and eicosapentaenoic (EPA) fatty acids, showed reduced accumulation of body fat and prevention of insulin resistance, besides increased mitochondrial beta-oxidation in white adipose tissue and decreased plasma lipids. ALA, EPA and DHA all belong to PUFA of n-3 series. The intestine is a gatekeeper organ for ingested lipids. To examine the potential contribution of the intestine in the beneficial effects of EPA and DHA, this study assessed gene expression changes using whole genome microarray analysis on small intestinal scrapings. The main biological process affected was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR and intestinal fatty acid oxidation measurements ([14C(U)]-palmitate) confirmed significant gene expression differences in a dose-dependent manner. Furthermore, no major changes in the expression of lipid metabolism genes were observed in colonic scrapings. In conclusion, we show that marine n-3 fatty acids regulate small intestinal gene expression patterns. Since this organ contributes significantly to whole organism energy use, this adaptation of the small intestine may contribute to the complex and observed beneficial physiological effects of these natural compounds under conditions that will normally lead to development of obesity and diabetes.
2009-04-01 | GSE11936 | GEO