Inhibition of Hepatic Acyl Coa Oxidase 1 (ACOX1), A Peroxisome Β-Oxidation Enzyme, Modifies Brain Fatty Acid Profile And Intrinsic Membrane Properties in Granule Cells of Rat Dentate Gyrus

Peroxisomes are the essential organelles in lipid metabolism. They contain enzymes for β-oxidation of very-long-chain fatty acids, which cannot break down in mitochondria. A reduced expression in hepatic Acyl-CoA oxidase1 (ACOX1), a peroxisome β-oxidation enzyme, followed by modification of the brain fatty acid profile has been seen in aged rodents. These studies have suggested a potential role for peroxisome β-oxidation in brain aging. This study was designed to examine the effect of hepatic ACOX1 inhibition on brain fatty acid composition and neuronal cell activities of young rats (200-250 g). A specific ACOX1 inhibitor, 10, 12- tricosadiynoic acid (TDYA), 100 μg/kg (in olive oil) was given by daily gavage administration for 25 days in male Wistar rats. The brain fatty acid composition and electrophysiological properties of dentate gyrus granule cells were determined by gas chromatography and whole-cell patch-clamp, respectively. A significant increase in C20, C22, C18:1, C20:1, and a decrease of C18, C24, C20:3n6 and C22:6n3 were found in TDYA treated rats compared to the control group. The results show that ACOX1 inhibition changes fatty acid composition similar to old rats. ACOX1 inhibition caused hyperpolarization of resting membrane potential, and also reduction of input resistance, action potential duration, and spike firing. Moreover, ACOX1 inhibition increased rheobase current and afterhyperpolarization amplitude in granule cells. The results indicate, systemic inhibition of ACOX1 causes hypo-excitability of neuronal cells. These findings provide a new evidence on the involvement of peroxisome function and hepatic ACOX1 activity in brain fatty acid profile and the electrophysiological properties of dentate gyrus cells.