Fuel availability and fate in cardiac metabolism: A tale of two substrates

Abstract

The heart's extraordinary metabolic flexibility allows it to adapt to normal changes in physiology in order to preserve its function. Alterations in the metabolic profile of the heart have also been attributed to pathological conditions such as ischemia and hypertrophy; however, research during the past decade has established that cardiac metabolic adaptations can precede the onset of pathologies. It is therefore critical to understand how changes in cardiac substrate availability and use trigger events that ultimately result in heart dysfunction. This review examines the mechanisms by which the heart obtains fuels from the circulation or from mobilization of intracellular stores. We next describe experimental models that exhibit either an increase in glucose use or a decrease in FA oxidation, and how these aberrant conditions affect cardiac metabolism and function. Finally, we highlight the importance of alternative, relatively under-investigated strategies for the treatment of heart failure. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

Keywords: Cardiac metabolism; Fatty acid oxidation; Glucose oxidation; Hypertrophy; Substrate switching; Substrate uptake; Ventricular function.

Figure 1

Proposed role of endothelial metabolism in regulating cardiac substrate use. The metabolism of exogenous FA and glucose within endothelial cells may determine FA availability at the cardiomyocyte sarcolemma, thereby regulating cardiac substrate selection and cardiomyocyte energy metabolism. Albumin (Alb)-bound fatty acids (FAs) derived from the circulation and those hydrolyzed by lipoprotein lipase (LpL) at the cell surface enter endothelial cells assisted by the membrane proteins CD36 and FABPpm, a mechanism enhanced by acyl-CoA synthetase (ACS)-mediated vectorial acylation. ACS-mediated activation of FAs has additional roles: the generation of energy via FA β-oxidation for FA transport, or the esterification of FAs to complex lipids for storage and subsequent hydrolysis and vesicular or other transendothelial trafficking to the basolateral membrane for export. Glucose transport through endothelial cells requires both HIF1α and GLUT1, but the underlying mechanism has not been elucidated. Solid lines indicate published data supports this mechanism, whereas dashed arrows are used to denote an unknown mechanism.