Metabolic fingerprints of human primary endothelial and fibroblast 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, to shunt glucose to side branches of glycolysis, to provide energy more rapidly, or to use the most abundant fuel available. 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. The lipid mediators most likely responsible are diacylglycerols and ceramides, which are associated with insulin resistance in these tissues. 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 with vascular dysfunction. Hyperlipidemia is closely linked to nutrient overload and insulin resistance and is a major contributor to cardiovascular disease. Increased intestinal nutrient handling is one process that contributes to dyslipidemia. For example, intestinal biopsies from obese insulin-resistant human subjects exhibit exaggerated triglyceride-rich lipoprotein (TRL) production, when compared with obese insulin–sensitive subjects, through a mechanism that may involve reduced insulin signaling in the intestine. Fructose was found to be particularly apt to increase TRLs in human subjects. The liver takes up TRLs and, in turn, produces very low–density lipoproteins (VLDL) through the action of the enzyme acyl-CoA:diacylglycerol acyltransferase 2. Increased VLDL and reduced high-density lipoprotein cholesterol levels are characteristics of metabolic syndrome and diabetes mellitus. Hyperglycemia occurs in subjects with metabolic syndrome and diabetes mellitus and is often associated with dyslipidemia and other cardiovascular risk factors and endothelial dysfunction. It is still unclear to what extent hyperglycemia, directly or indirectly, contributes to cardiovascular disease in human subjects. It is, however, becoming increasingly evident that glucose metabolites play important regulatory roles in cellular activation, which is often dysfunctional in diabetes mellitus. Is the cardiovascular disease associated with metabolic syndrome and type 2 diabetes mellitus explained by systemic factors, such as low-grade inflammation, increased adiposity, defective insulin signaling, hypertension, and dyslipidemia, or do metabolic flexibility and dysfunction in vascular and cardiac cells themselves contribute to cardiovascular pathologies? Recent advances in the research area of metabolism in cell types involved in cardiovascular disease are highlighted in this article, with special emphasis on recent research published in ATVB.