Metabolic Flexibility and Dysfunction in Cardiovascular Cells

Cardiovascular cells that contribute directly to atherosclerosis and cardiac dysfunction are known to exhibit metabolic flexibility, characterized by the ability to switch from generating ATP primarily through oxidative phosphorylation to using glycolysis as the predominate energy source, and to shift from one fuel source to another. This flexibility occurs in endothelial cells (ECs), myeloid cells, and cardiomyocytes during normal development and physiology, and is thought to have evolved to protect cells with heightened energy demand from the increased oxidative stress that can be a result of oxidative phosphorylation,1 to shunt glucose to side branches of glycolysis,2 to provide energy more rapidly,1 or to use the most abundant fuel available.3 With the growing problem of systemic nutrient overload and associated insulin resistance, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, metabolic flexibility and dysfunction in cells involved in cardiovascular disease have received increased attention as possible contributors to systemic inflammation and cardiovascular risk associated with these states.Systemic insulin resistance is thought to be due primarily to nutrient overload in skeletal muscle and liver as a consequence of an inability of adipose tissue to store excess nutrients in the form of triacylglycerol-rich lipid droplets, and a subsequent increase in detrimental lipid species in liver and skeletal muscle, which are inadequately equipped to store large amounts of lipid. Accumulation of noxious lipids leads to dysfunction in liver and skeletal muscle cells characterized by insulin resistance, increased activation of the unfolded protein response, and increased production of inflammatory mediators.4–6 The lipid mediators most likely responsible are diacylglycerols and ceramides, which are associated with insulin resistance in these tissues.5 Insulin resistance is well known to be associated with increased cardiovascular risk. Furthermore, accumulation of hepatic lipids in subjects with nonalcoholic fatty liver disease is associated …