Differential Metabolism of Octanoate by Liver, Heart and Muscle and the Failure of Dietary Octanoate to Rescue Mitochondrial Long‐chain Fatty Acid Oxidation‐Deficient Cardiac Hypertrophy

Abstract

Long-chain fatty acids are critical energetic substrates for cardiac health. During metabolic and heart disease when cardiac mitochondrial oxidative metabolism is impaired, the use of regularly minor energetic substrates, such as ketones and medium-chain fatty acids, could be beneficial for rescuing cardiac function. Here we tested the ability of dietary octanoate, an eight-carbon medium-chain fatty acid, to rescue cardiac hypertrophy in a mouse model of impaired mitochondrial long-chain fatty acid oxidation, the cardiac Carnitine Palmitoyltransferase 2 deficient mice (Cpt2M-/-). CPT2 is a critical enzyme of the acylcarnitine shuttle that converts acylcarnitine moieties to acyl-CoAs in the mitochondrial matrix for subsequent oxidation. In Cpt2M-/- mice, high octanoate-ketogenic diet failed to alleviate hypertrophy, improve cardiac function, or rescue cardiac accumulation of long-chain acylcarnitines. To understand this lack of phenotypic rescue, we found that heart and skeletal muscle mitochondria were unable to oxidize free octanoate, whereas liver mitochondria readily oxidized free octanoate. Liver mitochondria highly expressed medium-chain acyl-CoA synthetases, enabling octanoate activation for oxidation independent of the acylcarnitine-shuttle, whereas no expression was detected in heart or skeletal muscle. Conversely, the carnitine ester of octanoate, octanoyl-carnitine, was readily oxidized by liver, skeletal muscle, and heart, with heart oxidation rates being 4-fold greater than liver. Furthermore, we found that octanoyl-carnitine oxidation in muscle occurred independent of CPT2 enzyme. These data demonstrate that dietary intervention with the medium chain fatty acid octanoate cannot rescue the impairments caused by CPT2-deficiency in the heart questioning the bioavailability of dietary octanoate for the heart. These data also demonstrate that liver oxidizes free octanoate independent of carnitine, and that cardiac and skeletal muscle depend on carnitine, but not CPT2, for octanoate oxidation.