L-Carnitine Improves Skeletal Muscle Fat Oxidation in Primary Carnitine Deficiency
Karen L. MadsenNicolai PreislerJan RasmussenGitte HedermannJess Have OlesenAllan M. LundJohn Vissing
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Abstract:
Primary carnitine deficiency (PCD) is an inborn error of fatty acid metabolism. Patients with PCD are risk for sudden heart failure upon fasting or illness if they are not treated with daily l-carnitine. To investigate energy metabolism during exercise in patients with PCD with and without l-carnitine treatment. Interventional study. Hospital exercise laboratories and department of cardiology. Eight adults with PCD who were homozygous for the c.95A>G (p.N32S) mutation and 10 healthy age- and sex-matched controls. Four-day pause in l-carnitine treatment. Total fatty acid and palmitate oxidation rates during 1-hour submaximal cycle ergometer exercise assessed with stable isotope method (U13C-palmitate and 2H2-d-glucose) and indirect calorimetry with and without l-carnitine. Total fatty acid oxidation rate was higher in patients with l-carnitine treatment during exercise than without treatment [12.3 (SD, 3.7) vs 8.5 (SD, 4.6) µmol × kg−1 × min−1; P = 0.008]. However, the fatty acid oxidation rate was still lower in patients treated with l-carnitine than in the healthy controls [29.5 (SD, 10.1) µmol × kg−1 × min−1; P < 0.001] and in the l-carnitine group without treatment it was less than one third of that in the healthy controls (P < 0.001). In line with this, the palmitate oxidation rates during exercise were lower in the no-treatment period [144 (SD, 66) µmol × kg−1 × min−1] than during treatment [204 (SD, 84) µmol × kg−1 × min−1; P = 0.004) . The results indicate that patients with PCD have limited fat oxidation during exercise. l-Carnitine treatment in asymptomatic patients with PCD may not only prevent cardiac complications but also boost skeletal muscle fat metabolism during exercise.Keywords:
Fatty Acid Metabolism
Carbohydrate Metabolism
Fatty Acid Metabolism
Coenzyme A
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Fatty Acid Metabolism
Long chain
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Carnitine O-palmitoyltransferase
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We examined, in muscle of lean and obese Zucker rats, basal, insulin-induced, and contraction-induced fatty acid transporter translocation and fatty acid uptake, esterification, and oxidation. In lean rats, insulin and contraction induced the translocation of the fatty acid transporter FAT/CD36 (43 and 41%, respectively) and plasma membrane-associated fatty acid binding protein (FABPpm; 19 and 60%) and increased fatty acid uptake (63 and 40%, respectively). Insulin and contraction increased lean muscle palmitate esterification and oxidation 72 and 61%, respectively. In obese rat muscle, basal levels of sarcolemmal FAT/CD36 (+33%) and FABPpm (+14%) and fatty acid uptake (+30%) and esterification (+32%) were increased, whereas fatty acid oxidation was reduced (-28%). Insulin stimulation of obese rat muscle increased plasmalemmal FABPpm (+15%) but not plasmalemmal FAT/CD36, blunted fatty acid uptake and esterification, and failed to reduce fatty acid oxidation. In contracting obese rat muscle, the increases in fatty acid uptake and esterification and FABPpm translocation were normal, but FAT/CD36 translocation was impaired and fatty acid oxidation was blunted. There was no relationship between plasmalemmal fatty acid transporters and palmitate partitioning. In conclusion, fatty acid metabolism is impaired at several levels in muscles of obese Zucker rats; specifically, they are 1) insulin resistant with respect to FAT/CD36 translocation and fatty acid uptake, esterification, and oxidation and 2) contraction resistant with respect to fatty acid oxidation and FAT/CD36 translocation, but, conversely, 3) obese muscles are neither insulin nor contraction resistant at the level of FABPpm. Finally, 4) there is no evidence that plasmalemmal fatty acid transporters contribute to the channeling of fatty acids to specific metabolic destinations within the muscle.
CD36
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Fatty Acid Metabolism
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A quantitative gas chromatography-mass spectrometry (GC/MS) method was developed to measure nanomolar quantities of long-chain saturated beta-hydroxy fatty acids (12, 14, 16, and 18 carbons long) produced by isolated ischemic heart. Only beta-hydroxymyristate (25-40 nmol/g dry) was found in fresh heart. Isolated rabbit heart perfused with fatty acid by the nonrecirculating Langendorff technique produced negligible beta-hydroxy fatty acids. Ischemic perfusion with 0.25-0.75 mM palmitate prompted heart beta-hydroxy fatty acid accumulation, beta-hydroxypalmitate greater than beta-hydroxystearate, up to 100 nmol x g dry-1 x 10 min-1. beta-Hydroxy fatty acid production was proportional to coronary effluent lactate-to pyruvate ratio, did not continue beyond 10 min of ischemia, was dependent on exogenous fatty acid, and was inhibited by coperfusion with 10 mM acetate. Reperfusion for 5-10 min dissipated accumulated beta-hydroxypalmitate. Hypoxic perfusion prompted beta-hydroxy fatty acid production comparable to that with severe ischemia. These data show that during oxygen deficiency heart fatty acid beta-oxidation is not only depressed but is also incomplete; beta-hydroxy fatty acyl intermediates accumulate and contribute to the increased intracellular fatty acid content characteristic of the ischemic myocardium.
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Carnitine O-palmitoyltransferase
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Fatty Acid Metabolism
Lipid Oxidation
Fatty acid synthesis
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Background/Aim Fatty liver is closely associated with lifestyle‐related illness and liver diseases. However, the effective therapy for fatty liver has not been established yet. Carnitine is an essential factor to transport fatty acid into mitochondria. This study examined the effectiveness of carnitine on fatty acid catabolism in fatty liver culture cell model. Methods In human Fa2N4 and mouse AML12 cells, fatty liver induced by synthetic LXR‐ligand ( To901317 ) exposure was treated with 0–10 mM carnitine for 3 days. The levels of triglyceride (TG) and fatty acid metabolism‐related genes were evaluated. Further, normal cell was loaded to 200 μM parmitic acid with 1 mM carnitine for up to 20h, and β‐oxidation metabolites in medium was measured. Results In both cells, TG level was significantly and dose‐dependently decreased by carnitine treatment. The enhanced mRNA levels of SREBP‐1, ACC, FAS, and SCD were significantly decreased by carnitine. After 20h of fatty acid load, ketone body excretion from cell was significantly increased with carnitine compared to that without carnitine. The mRNA levels of PPARα, CPT‐1α, PGC‐1α, and OCTN2 were significantly increased after 20h compared to these at 0 time. Conclusion In the cell model, fatty liver was improved by carnitine treatment through β‐oxidation activation. Therefore, carnitine administration would be a possible therapy for metabolic syndrome with fatty liver.
Catabolism
Fatty Acid Metabolism
Steatosis
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The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges.
Fatty Acid Metabolism
Adenosine triphosphate
Fatty acid synthesis
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