scholarly journals Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2703
Author(s):  
Lars Kaiser ◽  
Isabel Quint ◽  
René Csuk ◽  
Manfred Jung ◽  
Hans-Peter Deigner
Keyword(s):  
Reactive Oxygen Species ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Energy Production ◽  
Hematopoietic Cells ◽  
Reactive Oxygen ◽  
Health Concern ◽  
Acid Oxidation ◽  
Oxygen Species ◽  
Ethylhexyl Phthalate

Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An analysis of the underlying mechanism revealed that MEHP promotes increases in reactive oxygen species (ROS) by reducing the activity of superoxide dismutase in all lineages, possibly via its actions at the aryl hydrocarbon receptor. This leads to a metabolic shift away from glycolysis toward the pentose phosphate pathway and ultimately results in the death of hematopoietic cells that rely on glycolysis for energy production. By contrast, cells that utilize fatty acid oxidation for energy production are not susceptible to this outcome due to their capacity to uncouple ATP production. These responses were also detected in non-hematopoietic cells exposed to alternate inducers of ROS.

scholarly journals Active fatty acid oxidation defines the cellular response towards reactive oxygen species

2020 ◽  
Author(s):  
Lars Kaiser ◽  
Isabel Quint ◽  
René Csuk ◽  
Manfred Jung ◽  
Hans-Peter Deigner
Keyword(s):  
Reactive Oxygen Species ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cellular Response ◽  
Reactive Oxygen ◽  
Endocrine Disrupting Compounds ◽  
Acid Oxidation ◽  
Oxygen Species ◽  
Atp Generation ◽  
The Impact

AbstractEndocrine disrupting compounds (EDC) are ubiquitous in the human environment, displaying a highly relevant research topic. The impact of EDC on the differentiation of primitive cells, e.g. in hematopoiesis, is of particular interest. We found profound inhibitory effects of di-2-ethylhexyl phthalate (DEHP) on erythropoiesis and dendropoiesis, mediated via reactive oxygen species (ROS) generation. Neutrophil differentiation, however, was not affected by DEHP. ROS leads to a shift from glycolysis to the pentose phosphate pathway and diminishes ATP generation from glycolysis, ultimately resulting in apoptosis in both cell types. In neutrophils, ATP generation is held constant by active fatty acid oxidation (FAO), rendering these cells highly resistant against ROS. This relationship also holds true in HUVEC and HepG2 cells, also in combination with other organic peroxides. We, therefore, uncover a key mechanism for ROS quenching which further explains the distinct ROS quenching ability of different tissues.

scholarly journals Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Pallavi Chandra ◽  
Li He ◽  
Matthew Zimmerman ◽  
Guozhe Yang ◽  
Stefan Köster ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Oxygen Species ◽  
Content Type ◽  
Mitochondrial Fatty Acid

ABSTRACT Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages, and its growth was attenuated in mice. Mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the leading infectious disease killer worldwide. We discovered that intracellular Mtb fails to grow in macrophages in which fatty acid β-oxidation (FAO) is blocked. Macrophages treated with FAO inhibitors rapidly generate a burst of mitochondria-derived reactive oxygen species, which promotes NADPH oxidase recruitment and autophagy to limit the growth of Mtb. Furthermore, we demonstrate the ability of trimetazidine to reduce pathogen burden in mice infected with Mtb. These studies will add to the knowledge of how host metabolism modulates Mtb infection outcomes.

scholarly journals Nifedipine Modulates Renal Lipogenesis via the AMPK-SREBP Transcriptional Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1570 ◽  
Author(s):  
Yen-Chung Lin ◽  
Mai-Szu Wu ◽  
Yuh-Feng Lin ◽  
Chang-Rong Chen ◽  
Chang-Yu Chen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Accumulation ◽  
Coenzyme A ◽  
Surrogate Marker ◽  
Reactive Oxygen ◽  
Fatty Acyl ◽  
Acid Oxidation ◽  
Oxygen Species ◽  
Atp Production ◽  
Renal Tubular Cells

Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.

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