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

Abstract

Endocrine disrupting compounds (EDC) are found ubiquitous in the human environment, displaying a highly relevant research topic. Here, the impact of EDC on the differentiation of primitive cells, e.g. hematopoiesis, is of particular interest. We therefore assessed the impact of di-2-ethylhexyl phthalate (DEHP) on erythroid, dendritic and neutrophil differentiation and found profound inhibitory effects of DEHP on erythropoiesis and dendropoiesis, mediated via ROS generation. ROS leads to a shift from glycolysis to pentose phosphate pathway and diminishes ATP generation from glycolysis, ultimately resulting in apoptosis in both cell lines. In neutrophils, however, ATP generation is held constant by active fatty acid oxidation (FAO), rendering these cells highly resistant against ROS. As we could verify this relationship also in other tissues and, furthermore, with other compounds, we propose this to be a general mechanism. Therefore, future toxicological studies should also consider FAO activity to be involved in ROS quenching capability.

Metabolite Patterns in Human Myeloid Hematopoiesis Result from Lineage-Dependent Active Metabolic Pathways

“…Here, we combined a known HSPC expansion approach with distinct lineage differentiations from the literature, resulting in formation of erythrocytes, dendritic cells (DC) and neutrophils. Due to the initial expansion step, large cell numbers can be generated with this approach, making it highly suitable for omics-based toxicity testing (e.g., demonstrated in [50]). Further assessment of metabolic and transcriptional changes during lineage formation resulted in unique and common metabolite sets, reflecting distinct metabolic changes in several interconnected pathways (namely glycolysis, glutaminolysis, polyamine synthesis, fatty acid oxidation and synthesis, as well as glycerophospholipid and sphingolipid metabolism).…”