L-Carnitine is an amino acid derivative that is synthesised in the liver and the kidneys from the essential amino acids lysine and methionine, and it is the essential cofactor for the transport of the long-chain fatty acids into the mitochondrial matrix for beta-oxidation. The long-chain fatty acids (which are the primary fuel source for the heart, the skeletal muscle, and the liver) cannot cross the inner mitochondrial membrane directly — they must be converted to the acylcarnitine esters by the carnitine palmitoyltransferase 1 (CPT1) enzyme on the outer mitochondrial membrane, and these acylcarnitine esters must then be transported across the inner mitochondrial membrane by the carnitine-acylcarnitine translocase (CACT) and converted back to the free fatty acids by the carnitine palmitoyltransferase 2 (CPT2) enzyme on the inner mitochondrial membrane. Without adequate L-carnitine, the fatty acids cannot enter the mitochondria for oxidation, they accumulate in the cytoplasm, and the cellular energy metabolism is severely compromised — producing the muscle weakness, the cardiac dysfunction, and the hepatic steatosis that are the hallmark of the carnitine deficiency. The dietary sources of L-carnitine include the red meat (which is the richest source), the dairy products, the fish, and the poultry, and the total body carnitine pool is approximately 20-25g in the average adult.
The Carnitine Shuttle and the Beta-Oxidation
The carnitine shuttle is the mechanism by which the long-chain fatty acids are transported into the mitochondrial matrix for beta-oxidation — it consists of three enzymatic steps. The first step is the formation of the acylcarnitine ester by the CPT1 enzyme on the outer mitochondrial membrane — the CPT1 transfers the acyl group from the CoA to the carnitine, forming the acylcarnitine and releasing the CoA. The second step is the transport of the acylcarnitine across the inner mitochondrial membrane by the CACT (the carnitine-acylcarnitine translocase), which exchanges the acylcarnitine for the free carnitine on a one-for-one basis. The third step is the conversion of the acylcarnitine back to the free fatty acid and the free carnitine by the CPT2 enzyme on the inner mitochondrial membrane — the CPT2 transfers the acyl group from the carnitine back to the CoA that is present in the mitochondrial matrix, forming the acyl-CoA and the free carnitine. The free carnitine is then transported back out of the mitochondria by the CACT, completing the carnitine shuttle cycle. Without the functional carnitine shuttle, the long-chain fatty acids cannot be oxidised, and the cellular energy production from the fat is severely impaired.
The clinical importance of the L-carnitine for the fatty acid oxidation is underscored by the observation that the primary carnitine deficiency (a genetic disorder in which the carnitine synthesis or the carnitine transport is impaired) produces a clinical syndrome that includes the hypoglycaemia, the hyperammonaemia, the cardiomyopathy, the muscle weakness, and the developmental delay — all of which are the direct result of the impaired fatty acid oxidation and of the resulting energy failure. The secondary carnitine deficiency (which is more common and which is associated with the valproic acid therapy, the renal dialysis, the cirrhosis, and the inborn errors of the organic acid metabolism) produces a milder form of the same clinical syndrome, and it is corrected by the L-carnitine supplementation at 50-100mg/kg daily.
L-Carnitine and the Cardiac Function
The heart is one of the organs that is most dependent on the fatty acid oxidation for its energy needs — it oxidises the fatty acids to generate approximately 60-70% of its ATP, with the remaining 30-40% coming from the glucose and from the lactate. The L-carnitine is therefore particularly important for the cardiac function — it is required for the transport of the fatty acids into the mitochondria of the cardiac muscle cells, and without adequate L-carnitine, the cardiac energy production is impaired and the cardiac contractile function is compromised. The L-carnitine has been studied as a treatment for the congestive heart failure (CHF) — multiple RCTs have demonstrated that L-carnitine supplementation at 2-3g daily improves the exercise tolerance, reduces the symptoms of the CHF (dyspnoea, fatigue, peripheral oedema), and improves the left ventricular ejection fraction in patients with the CHF. The proposed mechanism of this benefit involves the restoration of the normal fatty acid oxidation in the cardiac muscle, the reduction of the ischaemic damage to the myocardium, and the improvement of the cardiac contractile efficiency.
Practical Application
For general L-carnitine supplementation, the evidence-based approach is to supplement with 1-3g of L-carnitine daily (as the L-carnitine L-tartrate or as the acetyl-L-carnitine form — the ALCAR form is preferred for the brain, because it crosses the blood-brain barrier more efficiently than the L-carnitine). The L-carnitine is generally well-tolerated with no significant adverse effects at doses up to 3g daily, though very high doses may produce the gastrointestinal symptoms (nausea, abdominal cramps, diarrhoea) or the fishy body odour (from the trimethylamine that is produced by the gut microbiota from the unabsorbed carnitine). For the treatment of the primary carnitine deficiency, the L-carnitine supplementation at 100-200mg/kg daily is used (under the supervision of a physician). For comprehensive fatty acid oxidation and energy support, L-carnitine pairs well with the alpha-lipoic acid (which is a cofactor for the pyruvate dehydrogenase and the alpha-ketoglutarate dehydrogenase enzymes and which has complementary effects on the mitochondrial energy metabolism), with the CoQ10 (which is required for the electron transport chain and which is regenerating vitamin E), and with the magnesium (which is required for the function of the ATP-consuming enzymes and which is often deficient in people with the mitochondrial dysfunction).
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