Molecular Genetics

Cardiac energy metabolism and chronic cardiac disease

The aim of the programme is to disclose the mechanisms underlying the process of metabolic (mal)adaptation and its relation to cardiac (dys)function in pathophysiological conditions such as diabetic cardiomyopathy (DCM) and Wolff-Parkinson-White (WPW) syndrome (glycogen storage disease). DCM is common in type 2 diabetes and results from the adaptation of the insulin-resistant heart towards an increased utilization 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 (cytokines, high-fat diet, 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 (‘metabolic modulation’), by manipulating the sarcolemmal presence and activity of substrate transporters for fatty acids and for glucose, and by reducing the adverse affects of substrate intermediates on mitochondrial function. In the WPW syndrome glycogen utilization is impaired which becomes manifest in a markedly reduced (flexibility of) cardiac function. The hypothesis is studied that this is the result of a defect in the interaction between AMP kinase and glycogen.

Publications (selection)

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 transporets 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

Glatz JFC, Angin Y, Steinbusch LKM, Schwenk RW, Luiken JJFP. CD36 as target to prevent cardiac lipotoxicity and insulin resistance. Prostagl Leukotr Essent Fatty Acids 88: 71-77, 2013

Chen L, Xin F-J, Wang J, Hu J, Zhang Y-Y, Wan S, Cao L-S, Lu C, Li P, Yan SF, Neumann D, Schlattner U, Xia B, Wang Z-X, Wu J-W. Conserved regulatory elements in AMPK. Nature 498: E8-E10, 2013

Pelsers MMAL, Hermens WT, Glatz JFC. Fatty acid-binding proteins as plasma markers of tissue injury. Clin Chim Acta 352: 15-35, 2005.

Team leader

Prof. Jan Glatz

Research group

Joost J.F.P. Luiken, PhD, Will A. Coumans, Ricardo Rodriguez Calvo, PhD, Yvonne Oligschläger, PhD, Marie Miglianico, Xiaoqing Zhu, Yilin Liu