Fatty Acid Increases cAMP-dependent Lactate and MAO-B-dependent GABA Production in Mouse Astrocytes by Activating a G(αs) Protein-coupled Receptor

Medium-chain fatty acids (MCFAs) are mostly generated from dietary triglycerides and can penetrate the blood-brain barrier. Astrocytes in the brain use MCFAs as an alternative energy source. In addition, MCFAs have various regulatory and signaling functions in astrocytes. However, it is unclear how astrocytes sense and take up MCFAs. This study demonstrates that decanoic acid (DA; C10), a saturated MCFA and a ligand of G(αs) protein-coupled receptors (G(αs)-GPCRs), is a signaling molecule in energy metabolism in primary astrocytes. cAMP synthesis and lactate release were increased via a putative G(αs)-GPCR and transmembrane adenylyl cyclase upon short-term treatment with DA. By contrast, monoamine oxidase B-dependent gamma-aminobutyric acid (GABA) synthesis was increased in primary cortical and hypothalamic astrocytes upon long-term treatment with DA. Thus, astrocytes respond to DA by synthesizing cAMP and releasing lactate upon short-term treatment, and by synthesizing and releasing GABA upon long-term treatment, similar to reactive astrocytes. Our data suggest that astrocytes in the brain play crucial roles in lipid-sensing via GPCRs and modulate neuronal metabolism or activity by releasing lactate via astrocyte-neuron lactate shuttle or GABA to influence neighboring neurons.

Comparative Study of in vivo Gastrointestinal Absorption of Mustard Oil Emulsions Prepared with Different Types of Medium Chain Fatty Acids

Absorption of dietary fats is generally in the form of emulsions. The present study assessed the preparation and gastrointestinal absorption efficiency of three emulsions of mustard oil containing three types of medium chain fatty acids (MCFAs) in a rat model. Methods: Caprylic acid (C8:0), capric acid (C10:0) and lauric acid (C12:0) were chosen as the MCFAs. Mustard oil emulsions were formulated using each of the MCFAs and lecithin as an emulsifier. The characteristics of the formulations including optical microscopy, particle size, zeta potential analysis and viscosity studies were assessed. Thereafter the intestinal digestion patterns of the three MCFA rich mustard oil emulsions were compared using a single pass perfusion test. Results: The particle size of the emulsions varied between 212.70 nm and 312.70 nm. Physical characterisation such as a zeta potential study confirmed that all emulsions were thermodynamically stable. The absorption study was monitored at 30 min intervals of up to 2 h The absorption of C8:0 emulsion was found to be maximum (27.78%) followed by C10:0 emulsion (24.81%) and C12:0 emulsion (22.50%). The differences in absorption efficiency of the emulsions could be attributed to the smaller chain length of C8:0 which was more rapidly absorbed by the intestine. Conclusion: In vivo gastrointestinal absorption of MCFA rich mustard oil emulsions was compared; caprylic acid-rich mustard oil showed the highest absorption rate in comparison to the other two emulsions. Further in vivo studies are required to establish the mechanism of absorption of structured lipids containing MCFAs.

Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

Abstract Fatty acid oxidation defects (FAODs) are inherited metabolic disorders caused by deficiency of specific enzyme activities or transport proteins involved in the mitochondrial catabolism of fatty acids. Medium-chain fatty acyl-CoA dehydrogenase (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies are relatively common FAOD biochemically characterized by tissue accumulation of medium-chain fatty acids and long-chain 3-hydroxy fatty acids and their carnitine derivatives, respectively. Patients with MCAD deficiency usually have episodic encephalopathic crises and liver biochemical alterations especially during crises of metabolic decompensation, whereas patients with LCHAD deficiency present severe hepatopathy, cardiomyopathy, and acute and/or progressive encephalopathy. Although neurological symptoms are common features, the underlying mechanisms responsible for the brain damage in these disorders are still under debate. In this context, energy deficiency due to defective fatty acid catabolism and hypoglycemia/hypoketonemia has been postulated to contribute to the pathophysiology of MCAD and LCHAD deficiencies. However, since energetic substrate supplementation is not able to reverse or prevent symptomatology in some patients, it is presumed that other pathogenetic mechanisms are implicated. Since worsening of clinical symptoms during crises is accompanied by significant increases in the concentrations of the accumulating fatty acids, it is conceivable that these compounds may be potentially neurotoxic. We will briefly summarize the current knowledge obtained from patients with these disorders, as well as from animal studies demonstrating deleterious effects of the major fatty acids accumulating in MCAD and LCHAD deficiencies, indicating that disruption of mitochondrial energy, redox, and calcium homeostasis is involved in the pathophysiology of the cerebral damage in these diseases. It is presumed that these findings based on the mechanistic toxic effects of fatty acids may offer new therapeutic perspectives for patients affected by these disorders.