Cardiac energy metabolism and chronic cardiac disease
There is growing recognition of the importance and multiple roles of substrate energy metabolism in both cardiac health and disease: cardiac metabolism is clearly moving center stage. Cardiac diseases are frequently accompanied by altered metabolism, while conversely, chronic changes in myocardial substrate preference are found to elicit cardiac contractile dysfunction. The predominant cardiac energy substrates are long-chain fatty acids and glucose. Strikingly, in the healthy heart there is an optimal balance between the uptake of fatty acids (mainly mediated by the membrane transporter protein CD36/SR-B2) and that of glucose (mainly mediated by the transporter GLUT4). Several frequently occurring cardiac diseases are characterized by a deviation from this optimal substrate balance. Such substrate shift may occur towards either direction, i.e., predominant utilization of fatty acids as seen in diabetic cardiomyopathy (DCM) or of glucose as in pressure overload-induced cardiac hypertrophy. The aim of this research program is to disclose the mechanisms underlying the maladaptive substrate shift, and to use the obtained mechanistic insights for so-called metabolic modulation therapy. Recently, gender differences in cardiac metabolism have also become a focus of research
Dr. Miranda Nabben en Dr. Joost Luiken
Cardiac Metabolism Maastricht Research group
Martijn Hoes (Assistant Professor), Francesco Schianchi (PhD student), Fang Wang (PhD student), Myrthe Willemars (PhD student), TingTing Zhang (PhD student)
DCM is common in type 2 diabetes and results from the adaptation of the insulin-resistant heart towards an increased use of fatty acids for energy production, at the expense of glucose. The increased fatty acid uptake rate leads to intracellular accumulation of lipids and toxic lipid intermediates (lipotoxicity) which aggravate insulin resistance (further diminished glucose uptake) and mitochondrial function, leading to severe cardiac dysfunction. Central in the research program are (i) the roles of external and environmental factors (high-fat diet, inflammatory conditions, etc.) in the development of DCM, and (ii) the development of strategies to normalize the substrate balance in the diabetic heart, i.e., lower fatty acid uptake and increase glucose utilization by manipulating the sarcolemmal presence and activity of substrate transporters, and by reducing the adverse effects of substrate intermediates on mitochondrial function.
Pressure overload-induced cardiac hypertrophy is accompanied by a shift of myocardial energy provision towards increased glucose utilization, at the expense of fatty acids. Strategies to re-balance the altered substrate preference, i.e., by limiting glucose utilization and/or increase fatty acid utilization, are being designed and studied, and showed promising results as therapeutic approach to improve cardiac contractile function.
Besides fatty acids and glucose, ketone bodies and amino acids serve as additional substrates for cardiac energy provision. How the myocardial uptake of these substrates is regulated and how they affect cardiac contractile function has recently become subject of study.
The research group routinely applies a large number of model systems and state-of-the-art techniques, several of these having been developed by the group itself. The model systems include freshly isolated cardiomyocytes from rodents, cardiomyocytes in culture and induced pluripotent human stem cells differentiated into cardiomyocytes.
Luiken JJFP, Koonen DPY, Willems J, Zorzano A, Becker C, Fischer Y, Tandon NN, Van der Vusse GJ, Bonen A, Glatz JFC. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes 51: 3113-3119, 2002.
Glatz JFC, Luiken JJFP, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism (Review). Physiol Rev 90: 367-417, 2010.
Dirkx E, Schwenk RW, Coumans WA, Hoebers N, Angin Y, Viollet B, Bonen A, Van Eys GJJM, Glatz JFC, Luiken JJFP. Protein kinase D1 is essential for contraction-induced glucose uptake, but is not involved in fatty acid uptake into cardiomyocytes. J Biol Chem 287: 5871-5881, 2012
Abdurrachim D, Luiken JJFP, Nicolay K, Glatz JFC, Prompers JJ, Nabben M. Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models. Cardiovasc Res 106: 194-205, 2015.
Liu Y, Steinbusch LKM, Nabben M, Kapsokalyvas D, van Zandvoort M, Schönleitner P, Antoons G, Simons PJ, Coumans WA, Geomini A, Chanda D, Glatz JFC, Neumann D, Luiken JJFP. Palmitate-induced vacuolar-type H+-ATPase inhibition feeds forward into insulin resistance and contractile dysfunction. Diabetes 66: 1521-1534, 2017.
Glatz JFC, Luiken JJFP. Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization. J Lipid Res 59: 1084-1093, 2018.
Geraets IME, Glatz JFC, Luiken JJFP, Nabben M. Pivotal role of membrane substrate transporters on the metabolic alterations in the pressure-overloaded heart. Cardiovasc Res 115: 1000-1012, 2019.
Glatz JFC, Nabben M, Young ME, Schulze PC, Taegtmeyer H, Luiken JJFP. Re-balancing cellular energy substrate metabolism to mend the failing heart. Biochim Biophys Acta, in press, 2020.