Basic Res Cardiol. 2000 Apr.
Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions.
Calvani M, Reda E, Arrigoni-Martelli E.
Sigma-Tau S.p.A., Rome.
[ PubMed ]

Abstract: This review focuses on the regulation of myocardial fatty acids and glucose metabolism in physiological and pathological conditions, and the role of L-carnitine and of its derivative, propionyl-L-carnitine. Fatty acids are the major oxidation fuel for the heart, while glucose and lactate provide the remaining need. Fatty acids in cytoplasm are transformed to long-chain acyl-CoA and transferred into the mitochondrial matrix by the action of three carnitine dependent enzymes to produce acetyl-CoA through the beta-oxidation pathway. Another source of mitochondrial acetyl-CoA is from the oxidation of carbohydrates. The pyruvate dehydrogenase (PDH) complex, the key irreversible rate limiting step in carbohydrate oxidation, is modulated by the intra-mitochondrial ratio acetyl-CoA/CoA. An increased ratio results in the inhibition of PDH activity. A decreased ratio can relieve the inhibition of PDH as shown by the transfer of acetyl groups from acetyl-CoA to carnitine, forming acetylcarnitine, a reaction catalyzed by carnitine acetyl-transferase. This activity of L-carnitine in the modulation of the intramitochondrial acetyl-CoA/CoA ratio affects glucose oxidation. Myocardial substrate metabolism during ischemia is dependent upon the severity of ischemia. A very severe reduction of blood flow causes a decrease of substrate flux through PDH. When perfusion is only partially reduced there is an increase in the rate of glycolysis and a switch from lactate uptake to lactate production. Tissue levels of acyl-CoA and long-chain acylcarnitine increase with important functional consequences on cell membranes. During reperfusion fatty acid oxidation quickly recovers as the prevailing source of energy, while pyruvate oxidation is inhibited. A considerable body of experimental evidence suggests that L-carnitine exert a protective effect in in vitro and in vivo models of heart ischemia and hypertrophy. Clinical trials confirm these beneficial effects although controversial results are observed. The actions of L-carnitine and propionyl-L-carnitine cannot be explained as exclusively dependent on the stimulation of fatty acid oxidation but rather on a marked increase in glucose oxidation, via a relief of PDH inhibition caused by the elevated acetyl-CoA/CoA ratio. Enhanced pyruvate flux through PDH is beneficial for the cardiac cells since less pyruvate is converted to lactate, a metabolic step resulting in the acidification of the intracellular compartment. In addition, L-carnitine decreases tissue levels of acyl moieties, a mechanism particularly important in the ischemic phase.

[Note: This may help explain the puzzle of the high acetylcarnitine (18.61, ref: <11.75) in the acylcarnitine profile of a 11-month-old baby, as he is on a formula with added L-carnitine (as is common nowadays because otherwise carnitine deficiency can develop on non-dairy formulas). That is, the L-carnitine is not just boosting fatty acid oxidation but is accepting acetyl groups from acetyl-CoA, thereby lowering the acetyl-CoA/CoA ratio, which in turn is causing a shift back to glucose oxidation. The question now is why is there a high acetyl-CoA/CoA ratio in PWS?

This may also explain why another baby is reportedly doing much better on L-carnitine fumarate than acetyl-l-carnitine (ALC). After all, why give ALC when the acetyl-CoA/CoA ratio is high, since we would want to increase the level of free carnitine able to accept acetyl groups from acetyl-CoA in order to reduce the acetyl-CoA/CoA ratio and thereby facilitate the shift back to glucose oxidation. In other words, it may not just be the fumarate that did the trick for her, but the carnitine minus the acetyl moiety. Indeed, fumarate may have had nothing to do with her better response to L-carnitine fumarate.]