Multi-Omics Integrative Analysis Coupled to Control Theory and Computational Simulation of a Genome-Scale metabolic Model Reveal Controlling Biological Switches in Human Astrocytes Under Palmitic Acid-Induced Lipotoxicity

Abstract

Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatory pathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, broad studies, with a systemic point of view on the neurodegenerative role of PA and the neuro-protective mechanisms of tibolone are lacking. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also applied a control theory approach to identify those reactions that exert more control in the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid β-oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation in metabolic pathways that may increase neurotoxicity and represent potential treatment targets. Finally, the overall framework of our approach facilitates the understanding of complex metabolic regulation, and it can be used for in silico exploration of the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.

Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases

“…These proteins participate in enriched metabolic pathways, such as fatty acid catabolism and the one-carbon folate cycle, and are present in cellular components, such as mitochondria and peroxisomes (Figure 1b) (Table S1 in the Supplementary Materials). Notably, these metabolic pathways are also known to be (de)regulated in human astrocytes under lipotoxic conditions because of the control exerted by these MSs [8]. Furthermore, previous studies have linked alterations in mitochondrial and peroxisomal fatty acid oxidation, along with other functions in these organelles, to the development of neuroinflammation and neurodegeneration [22][23][24][25].…”

“…According to the multi-omic computational model developed by [8], in the presence of PA, reactions such as the catalysis of the reversible transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP-producing 3-phosphoglycerate and ATP (PGK, EC. 2.7.2.3; UniProt ID: P00558) by phosphoglycerate kinase are partially inhibited [8]. At the level of the active site, this enzyme presents a cavity with strong druggable potential, thus being a potential therapeutic target.…”

“…The enzymatic metabolic switches analyzed in this study were identified in a previous study [8]. A description of all previously reported MSs can be found in Table S5 of the Supplementary Materials.…”

“…These cells regulate glutamate and ion homeostasis, cholesterol, and sphingolipid metabolism, and respond to environmental factors exerting neuroprotective effects maintaining general homeostasis of the nervous system [7]. Therefore, one of the crucial functions of astrocytes is their involvement in fatty acid metabolism [8]. Recent research has highlighted the significance of palmitic acid (PA), a long-chain saturated fatty acid that has been found to induce proinflammatory effects and reduce astrocyte viability, a condition known as lipotoxicity.…”

“…Consequently, the mathematical modeling of metabolic processes has facilitated the identification of crucial control sites and their contribution to the overall functionality of a given metabolic network. According to the most recent study conducted by our team [8], we identified 16 enzymatic metabolic switches in astrocytes treated with PA. Enzymatic metabolic switches (MSs) serve as critical control points, facilitating transitions between metabolic states and allowing cells to adapt to varying environmental cues and physiological demands. These switches play a fundamental role in both the regulation and deregulation of metabolic pathways in lipotoxic conditions, intensifying neurotoxicity, and potentially serving as valuable treatment targets.…”