Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions

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.

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

“…The major energy source of myocardium depends on the production of adenosine triphosphate (ATP) via oxidation of FFAs rather than glucose in aerobic metabolism34; however, ATP production shifts more to glycolysis in the anaerobic state that develops during myocardial ischemia,35 which results in increasing lactate and cytoplasmic calcium leading to the impaired generation of ATP 36, 37. Furthermore, catecholamine stimulation during myocardial ischemia increases the concentration of circulating FFAs as a result of lipolysis with the breakdown of triglycerides into FFAs and glycerol by catecholamine‐sensitive lipase in adipose tissue 38, 39.…”

Tissue-specific Short Chain Fatty Acid Metabolism and Slow Metabolic Recovery after Ischemia from Hyperpolarized NMR in Vivo

“…2C) or enzyme activities for acetyl-carnitine synthesis from exogenous acetate are reduced following ischemia and normalize only slowly. Earlier studies suggest that ischemic muscle exhibits a cellular build-up of free fatty acids and their activated acyl-CoA and acyl-carnitine esters (8,42,44,45). Free carnitine and CoA pools on the other hand decrease and get limiting to acetate metabolism, fatty acid oxidation, and pyruvate decarboxylation under conditions of low TCA cycle flux in ischemia, acute myocardial infarction and cardiac failure (9, 17, 46 -49).…”

Impact of Ischemia on Cellular Metabolism

“…In mild to moderate ischemia, the rate of fatty acid oxidation decreases but still fuels oxidative phosphorylation. [4], [24] In more severe ischemia, the lack of the cofactors NADH,H + and FAD + , which are normally regenerated through oxidative phosphorylation, completely inhibits acyl-CoenzymeA (acyl-CoA) dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase, which are key beta-oxidation enzymes. [4], [25] The cytosolic concentrations of fatty acids, acyl-CoA and acylcarnitine rise gradually.…”