Gary D. Lopaschuk

It has long been known that most of the energy production in the heart is derived from the oxidation of fatty acids. The other important sources of energy are the oxidation of carbohydrates and, to a lesser extent, ATP production from glycolysis. The contribution of these pathways to overall ATP production can vary dramatically, depending to a large extent on the carbon substrate profile delivered to the heart, as well as the presence or absence of underlying pathology within the myocardium. Despite extensive research devoted to the study of the individual pathways of energy substrate metabolism, relatively few studies have examined the integrated regulation between carbohydrate and fatty acid oxidation in the heart. While the mechanisms by which fatty acids inhibit carbohydrate oxidation (i.e., the Randle cycle) have been characterized, much less is known about how carbohydrates regulate fatty acid oxidation in the heart. It is clear that an increase in intramitochondrial acetyl-CoA derived from carbohydrate oxidation (via the pyruvate dehydrogenase complex) can downregulate β-oxidation of fatty acids, but it is not clear how fatty acid acyl group entry into the mitochondria is downregulated when carbohydrate oxidation increases. Recent interest in our laboratory has focused on the involvement of acetyl-CoA carboxylase (ACC) in this process. While it has been known for some time that malonyl-CoA does exist in heart tissue, and that it is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT 1), it has only recently been demonstrated that an isoenzyme of ACC exists in the heart that is a potential source of malonyl-CoA. These findings led to the hypothesis that ACC may be an important regulator of myocardial fatty acid oxidation. We have recently provided evidence that heart ACC, via the production of malonyl-CoA, can regulate fatty acid oxidation. We believe that ACC represents a key enzyme in a feedback loop that decreases acyl-CoA transport into the mitochondria when carbohydrate oxidation rates are increased. It is possible that ACC may represent a novel and potentially important site for pharmacological intervention in pathological situations characterized by abnormal fatty acid metabolism. This review provides a brief overview of the regulation of myocardial metabolism followed by our recent studies that support the hypothesis that ACC has an important role in regulating the balance between carbohydrate and lipid metabolism in the heart.Key words: fatty acids, glucose, malonyl-CoA, carnitine palmitoyltransferase 1, myocardial ischemia.

Between 1 and 7 days of life, the newborn rabbit heart shifts from predominantly using carbohydrates to predominantly using fatty acids as an energy substrate. We therefore used isolated working hearts from 1- or 7-day-old rabbits to determine the effects of fatty acids on myocardial glucose use and the ability of hearts to recover following various periods of transient no-flow ischemia. One-day-old hearts were perfused via the inferior vena cava and ejected buffer through the cannulated aorta and pulmonary artery. Seven-day-old hearts were perfused via the left atrium and ejected buffer through the cannulated aorta. To measure glucose use, hearts were perfused with 11 mM [ 3 H, 14 C]glucose, 3% albumin, and 500 μU insulin/mL, in the presence or absence of 0.4 mM palmitate. In the absence of fatty acids, glycolytic rates were similar in 1- and 7-day-old hearts, whereas glucose oxidation rates were 5 times greater in 7-day-old hearts. Palmitate did not have any major effects on overall glucose use in 1-day-old hearts, but did markedly inhibit glycolysis and glucose oxidation in 7-day-old hearts. A series of hearts were also subjected to periods (25–60 min) of no-flow ischemia, followed by 30 min of aerobic reperfusion. In the absence of palmitate, 1-day-old hearts subjected to ischemic periods of up to 60 min recovered some degree of mechanical function during reperfusion, whereas 7-day-old rabbit hearts failed to recover if hearts were subjected to ischemic periods of 35 min or longer. Palmitate did not affect reperfusion recovery of 1-day-old rabbit hearts, but did improve recovery of 7-day-old hearts subjected to 40 min of ischemia. This effect in 7-day-old hearts was accompanied by a decrease in tissue lactate during ischemia. In 1-day-old hearts, a greater increase in lactate levels at the end of ischemia was seen, compared with 7-day-old hearts, and the increase was unaffected by the presence or absence of palmitate. These results demonstrate that the sensitivity of the rabbit heart to ischemia increases in the 1st week after birth. This increased sensitivity may be related to a combination of a decrease in glycolytic rates and an increase in sensitivity of hearts to glycolytic product accumulation during ischemia.Key words: newborn, ischemia, heart, fatty acids, glucose.