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

Sarah Sonnay,Jonathan Thevenet,Nicolas Christinat,Andreas Wiederkehr,Mojgan Masoodi,Anirikh Chakrabarti

doi:10.3389/fphys.2019.00657

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-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.

Highlights

Medium-chain triglyceride (MCT) are hydrolyzed in the gut, which leads to an increase in the plasma concentrations of the medium chain fatty acids (MCFA) (i.e., C8:0 and C10:0) (Bernini et al, 2018)
These results indicate that both the rates of secretion and the total amounts of produced ketone bodies and butyrate are higher when astrocytes metabolize C8:0 compared to C10:0
Based on the differences observed on the redox ratio produced by the oxidation of C8:0 and C10:0 (Thevenet et al, 2016), and on the fact that administration of higher level MCT did not have a significant impact on the concentration of ketone bodies in the brain of traumatic brain injury (TBI) patients, as compared to a standard formula (Bernini et al, 2018), we aimed at tracking the basal production of βHB from C8:0 and C10:0 at the cellular level using metabolic flux analysis with 13C-labeled substrates

Summary

Introduction

Medium chain triglyceride-based (MCT) ketogenic diets are currently proposed as alternative brain energy substrates in conditions of limited cerebral glucose availability, such as in traumatic brain injury (TBI) (Prins and Matsumoto, 2014; Bernini et al, 2018), patients with glucose transporter 1 deficiency (Krass et al, 2016) and Alzheimer’s disease (Reger et al, 2004; Castellano et al, 2015; Cunnane et al, 2016; Croteau et al, 2018). MCFA cross the blood-brain barrier (Wlaź et al, 2015) and are oxidized in cells (Ebert et al, 2003) through β-oxidation for acetyl-CoA (AcCoA) generation and subsequent production of ketone bodies (Auestad et al, 1991), namely β-hydroxybutyrate (βHB) and acetoacetate (AcAc). Those produced ketone bodies can further be used as metabolic fuel by the brain (Nugent et al, 2014; Andersen et al, 2017; Evans et al, 2017)

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