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

Abstract

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- 13 C]-C8:0 or [U- 13 C]-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.

Decanoic Acid and Not Octanoic Acid Stimulates Fatty Acid Synthesis in U87MG Glioblastoma Cells: A Metabolomics Study

“…Hence, considering the lower level of OAA measured in C8 vs both CTR and C10-treated cells we can speculate that the acetyl-CoA derived from fatty acid oxidation could diverge toward ketone body synthesis, thus justifying the higher level of β-hydroxybutyrate and acetoacetate in C8- compared with both C10-treated cells and CTR cells. Our data are in accordance with those reported in Thevenet et al (2016) , Sonnay et al (2019) about the increased secretion of ketone bodies after C8- more than C10-addition to astrocytes. It should be noted that the Metabolic Pathway analysis indicates the synthesis and degradation of ketone bodies as a relevant pathway in C8-treated U87MG cells.…”

Efficacy and Safety of a Ketogenic Diet in Children and Adolescents with Refractory Epilepsy—A Review

“…MCTs are mainly composed of the unbranched fatty acids octanoic (C8:0) and decanoic (C10:0) acids which produce ketones [ 140 ]. Recent data reports conflicting results on seizure control potential of these medium chain fatty acid intermediates [ 141 , 142 , 143 ]. Brain cells treated with C8:0 produce larger amounts of ketone bodies and butyrate than C10:0 and application prior to seizure induction has been shown to increase seizure threshold [ 143 ] However, increased glutathione concentrations have been seen with cells incubated with C10:0 and increased seizure control has also been seen with C10:0 in an in vitro seizure model [ 141 , 142 ].…”

Ketosis After Intake of Coconut Oil and Caprylic Acid—With and Without Glucose: A Cross-Over Study in Healthy Older Adults

“…The specific ketogenic properties of C8which in our data are distinct from C12, and according to previous findings (12) also from C10-thus calls for an explanation beyond the aforementioned metabolic shortcuts. Different pathways for beta-oxidation have been suggested to underlie these variations (29).…”