The 1993 Merck Frosst Award. Acetyl-CoA carboxylase: an important regulator of fatty acid oxidation in the heart

Abstract

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.