AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart

Abstract

The heart relies predominantly on a balance between fatty acids and glucose to generate its energy supply. There is an important interaction between the metabolic pathways of these two substrates in the heart. When circulating levels of fatty acids are high, fatty acid oxidation can dominate over glucose oxidation as a source of energy through feedback inhibition of the glucose oxidation pathway. Following an ischaemic episode, fatty acid oxidation rates increase further, resulting in an uncoupling between glycolysis and glucose oxidation. This uncoupling results in an increased proton production, which worsens ischaemic damage. Since high rates of fatty acid oxidation can contribute to ischaemic damage by inhibiting glucose oxidation, it is important to maintain proper control of fatty acid oxidation both during and following ischaemia. An important molecule that controls myocardial fatty acid oxidation is malonyl-CoA, which inhibits uptake of fatty acids into the mitochondria. The levels of malonyl-CoA in the heart are controlled both by its synthesis and degradation. Three enzymes, namely AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and malonyl-CoA decarboxylase (MCD), appear to be extremely important in this process. AMPK causes phosphorylation and inhibition of ACC, which reduces the production of malonyl-CoA. In addition, it is suggested that AMPK also phosphorylates and activates MCD, promoting degradation of malonyl-CoA levels. As a result malonyl-CoA levels can be dramatically altered by activation of AMPK. In ischaemia, AMPK is rapidly activated and inhibits ACC, subsequently decreasing malonyl-CoA levels and increasing fatty acid oxidation rates. The consequence of this is a decrease in glucose oxidation rates. In addition to altering malonyl-CoA levels, AMPK can also increase glycolytic rates, resulting in an increased uncoupling of glycolysis from glucose oxidation and an enhanced production of protons and lactate. This decreases cardiac efficiency and contributes to the severity of ischaemic damage. Decreasing the ischaemic-induced activation of AMPK or preventing the downstream decrease in malonyl-CoA levels may be a therapeutic approach to treating ischaemic heart disease.