Metabolic therapy at the crossroad: how to optimize myocardial substrate utilization?

Abstract

There has been growing interest in targeting myocardial substrate metabolism for the therapy of cardiovascular and metabolic diseases. This is largely based on the observation that cardiac metabolism undergoes significant changes during both physiologic and pathologic stresses. In search for an effective therapeutic strategy, recent studies have focused on the functional significance of the substrate switch in the heart during stress conditions, such as cardiac hypertrophy and failure, using both pharmacologic and genetic approaches. The results of these studies indicate that both the capacity and the flexibility of the cardiac metabolic network are essential for normal function; thus, their maintenance should be the primary goal for future metabolic therapy.

Figure 1

Cardiac metabolic network for substrate utilization. Highlighted in solid colors are key regulatory sites for carbohydrates and lipids metabolism. The molecular targets of several transcriptional and/or signaling pathways in the regulation of substrate selection are also illustrated. ACC2: acetyl CoA carboxylase 2; ACS: acyl-coA synthetase; AMPK: adenosine monophosphate-activated protein kinase; ATP: adenosine triphosphate; CD36: cluster of differentiation 36 (fatty acid transporter); CPT1: carnitine palmitoyl transferase I; ETC: electron transport chain; FATP: fatty acid transport protein; G-6-P: glucose-6-phosphate; GLUT: glucose transporter; GYS: glycogen synthase; LDH: lactate dehydrogenase; MCD: malonyl CoA decarboxylase; MCT: monocarboxylate transporter; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PGC1-α: peroxisome proliferator-activated receptor-gamma coactivator 1 alpha; PPARα: peroxisome proliferator-activated receptor alpha; TAG: triacylglycerol; TCA: tricarboxylic acid cycle.