ACETYL-COA CARBOXYLASE - AN IMPORTANT REGULATOR OF FATTY-ACID OXIDATION IN THE HEART

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 sou rces of energy are the oxidation of carbohydrates and, to a lesser ext ent, ATP production from glycolysis. The contribution of these pathway s to overall ATP production can vary dramatically, depending to a larg e extent on the carbon substrate profile delivered to the heart, as we ll as the presence or absence of underlying pathology within the myoca rdium. Despite extensive research devoted to the study of the individu al pathways of energy substrate metabolism, relatively few studies hav e examined the integrated regulation between carbohydrate and fatty ac id oxidation in the heart. While the mechanisms by which fatty acids i nhibit carbohydrate oxidation (i.e., the Randle cycle) have been chara cterized, much less is known about how carbohydrates regulate fatty ac id oxidation in the heart. It is clear that an increase in intramitoch ondrial acetyl-CoA derived from carbohydrate oxidation (via the pyruva te dehydrogenase complex) can downregulate P-oxidation of fatty acids, but it is not clear how fatty acid acyl group entry into the mitochon dria is downregulated when carbohydrate oxidation increases. Recent in terest in our laboratory has focused on the involvement of acetyl-CoA carboxylase (ACC) in this process. While it has been known for some ti me that malonyl-CoA does exist in heart tissue, and that it is a poten t inhibitor of carnitine palmitoyltransferase 1 (CPT 1), it has only r ecently 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 decre ases acyl-CoA transport into the mitochondria when carbohydrate oxidat ion rates are increased. It is possible that ACC may represent a novel and potentially important site for pharmacological intervention in pa thological 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 carb ohydrate and lipid metabolism in the heart.