Differential Metabolism of Medium-Chain Fatty Acids in Differentiated Human-Induced Pluripotent Stem Cell-Derived Astrocytes

• Main Authors: Sarah Sonnay, Anirikh Chakrabarti, Jonathan Thevenet, Andreas Wiederkehr, Nicolas Christinat, Mojgan Masoodi
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-06-01
• Series: Frontiers in Physiology
• Subjects: β-oxidation; 13C-metabolic flux analysis; decanoic acid; induced pluripotent stem cell-derived astrocytes; octanoic acid
• Online Access: https://www.frontiersin.org/article/10.3389/fphys.2019.00657/full

Medium-chain triglyceride (MCT) ketogenic diets increase ketone bodies, which are believed to act as alternative energy substrates in the injured brain. Octanoic (C8:0) and decanoic (C10:0) acids, which produce ketone bodies through β-oxidation, are used as part of MCT ketogenic diets. Although the ketogenic role of MCT is well-established, it remains unclear how the network metabolism underlying β-oxidation of these medium-chain fatty acids (MCFA) differ. We aim to elucidate basal β-oxidation of these commonly used MCFA at the cellular level. Human-induced pluripotent stem cell-derived (iPSC) astrocytes were incubated with [U-13C]-C8:0 or [U-13C]-C10:0, and the fractional enrichments (FE) of the derivatives were used for metabolic flux analysis. Data indicate higher extracellular concentrations and faster secretion rates of β-hydroxybutyrate (βHB) and acetoacetate (AcAc) with C8:0 than C10:0, and an important contribution from unlabeled substrates. Flux analysis indicates opposite direction of metabolic flux between the MCFA intermediates C6:0 and C8:0, with an important contribution of unlabeled sources to the elongation in the C10:0 condition, suggesting different β-oxidation pathways. Finally, larger intracellular glutathione concentrations and secretions of 3-OH-C10:0 and C6:0 were measured in C10:0-treated astrocytes. These findings reveal MCFA-specific ketogenic properties. Our results provide insights into designing different MCT-based ketogenic diets to target specific health benefits.