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.

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.

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 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.​

Team leader
Prof. Jan F.C. Glatz
E: glatz@maastrichtuniversity.nl

 

Cardiac Metabolism Maastricht Research group

Joost J.F.P. Luiken, PhD (associate professor), Miranda Nabben PhD (assistant professor), Li-yen Wong, PhD (postdoc), Petra van der Molen (secretary), Agnieszka Strzelecka (technician), Bieke Vanherle (technician), Aomin Sun (PhD student), Shujin Wang (PhD student), Francesco Schianchi (PhD student), Berta Ganizada (PhD student), Petra van der Molen (administrative support).

Schools

GROW and CARIM

<foto’s van de gehele groep>

GCB_gastrointestinal_diseases_Ronit

Inflammation and lipid signaling for novel diagnosis and treatment of metabolic diseases

Lipids are a group of hydrophobic compounds that are generally found compartmentalized and serve as a major energy source of the body. Other lipid-related functions range from regulatory functions (i.e. hormones; bile acid precursors) to serving as structural component of the cell and its organelles (i.e. phospholipids and cholesterol). Due to these multiple functions, lipids play a central role in a large range of disorders. Among different physiological processes that are affected by lipid disturbances, inflammation is likely one of the most important. While designed to detect damage and foreign invading factors, the inflammatory response is dysregulated when lipid disturbances arise such as under obese conditions during which patients exhibit a chronic low-grade inflammatory response.

The goal of our research is to provide new diagnostic and therapeutic targets for a wide range of metabolic diseases (see figure below which diseases we focus on) by unraveling their pathometabolic basis. We collaborate with national and international public and private partners to accelerate the development of tangible products for patients.

Team leader:
Prof. Dr. Ronit Shiri-Sverdlov
E: r.sverdlov@maastrichtuniversity.nl

Research group members:
Dr. Tom Houben (assistant professor), Dr. Tim Hendrikx (shared postdoc with CeMM, Vienna), Dennis Meesters (lab manager / research assistant), Dr. Albert Bitorina (researcher), Tulasi Yadati (PhD student), Ines Reis (PhD student), Lingling Ding (PhD student), Annemarie Westheim (shared PhD student with Dr. Jan Theys), Mengying Li (PhD student), Petra van der Molen (administrative support).

Past group members:
Patrick van Gorp (lab manager), Kristiaan Wouters (PhD student), Veerle Bieghs (PhD student and Postdoc), Jieyi Li (PhD student), Mike Jeurissen (PhD student), Sofie Walenbergh (PhD student and Postdoc), Yvonne Oligschläger (postdoc).

Past PhD thesis defences within our group:
2020      Albert Bitorina, Inconspicuous offender: Pathophysiological role of oxidized-low density lipoprotein in metabolic diseases
2018     Tom Houben, Lysosomes ‘in control’: where lipids meet inflammation in metabolic syndrome
2017     Jieyi Li, Macrophage stimulating protein (MSP) in the metabolic syndrome
2017     Mike Jeurissen, The entanglement of NASH and atherosclerosis: shared features of a macrophage-specific response
2016     Sofie Walenbergh, Storage solutions: novel ways for the detection and inhibition of non-alcoholic steatohepatitis
2015     Tim Hendrikx, Intracellular traffic jam: cholesterol accumulation as cause for chronic inflammatory diseases
2011     Veerle Bieghs, Kupffer cells in fatty liver disease: Does size really matter?
2008     Kristiaan Wouters, Non-alcoholic steatohepatits: second hit or strike out?

Publications (selection):

  • Magro Dos Reis I, Houben T, Oligschläger Y, Bücken L, Steinbusch H, Cassiman D, Luetjohann D, Westerterp M, Prickaerts J, Plat J, Shiri-Sverdlov R. Dietary plant stanol ester supplementation reduces peripheral symptoms in a mouse model of Niemann-Pick type C1 disease. J Lipid Res. 2020 Apr 14.
  • ​Ding L, Goossens GH, Oligschlaeger Y, Houben T, Blaak EE, Shiri-Sverdlov R. Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans. Diabetologia. 2020 Feb;63(2):374-384.
  • Bitorina AV, Oligschlaeger Y, Shiri-Sverdlov R, Theys J. Low profile high value target: The role of oxLDL in cancer. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Dec;1864(12):15818.
  • ​Houben T, Oligschlaeger Y, Bitorina AV, Hendrikx T, Walenbergh SMA, Lenders MH, Gijbels, ​MJJ, Verheyen F, Lütjohann D, Hofker MH, Binder CJ, Shiri-Sverdlov R. Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation. Sci Rep 2017 Oct2;7(1):12550.
  • Hendrikx T, Watzenböck ML, Walenbergh SM, Amir S, Gruber S, Kozma MO, Grabsch HI, Koek GH, Pierik MJ, Staufer K, Trauner M, Kalhan SC, Jonkers D, Hofker MH, Binder CJ, Shiri-Sverdlov R; Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease. BMC Med 2016 Jul22;14(1).
  • Walenbergh SM, Houben T, Hendrikx T, Jeurissen ML, van Gorp PJ, Vreugdenhil AC, Adriaanse MP, Buurman WA, Hofker MH, Mosca A, Lindsey PJ, Alisi A, Liccardo D, Panera N, Koek GH, Nobili V, Shiri-Sverdlov R. Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation. Am J Gastroenterol 2015 Mar;110(3):462-70.
  • Bieghs V, Hendrikx T, van Gorp PJ, Verheyen F, Guichot YD, Walenbergh SM, Jeurissen ML, Gijbels M, Rensen SS, Bast A, Plat J, Kalhan SC, Koek GH, Leitersdorf E, Hofker MH, Lütjohann D, Shiri-Sverdlov R; The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 2013 Jan;144(1):167-178.e1.
  • Bieghs V, van Gorp PJ, Walenbergh SM, Gijbels MJ, Verheyen F, Buurman WA, Briles DE, Hofker MH, Binder CJ, Shiri-Sverdlov R; Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 2012 Sep;56(3):894-903.
  • Bieghs V, Wouters K, van Gorp PH, Gijbels MJ, de Winther MP, Binder CJ, Lütjohann D, Febbraio M, Moore KJ, van Bilsen M, Hofker MH, Shiri-Sverdlov R. Role of scavenger receptor A and CD36 in diet-induced non-alcoholic steatohepatits in hperlipidemic mice. Gastroenterology 2010 Jun;138(7):2477-86.
  • Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lütjohann D, Kerksiek A, van Kruchten R, Maeda N, Staels B, van Bilsen M, Shiri-Sverdlov R, Hofker MH. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of non-alcoholic steatohepatitis. Hepatology 2008 Aug;48(2):474-86.

Patents:

  • Methods for the treatment of nonalcoholic steatohepatitis; Patent No. TEMP/E-1/47465/2017.
  • Methods and compounds for the treatment of Niemann-Pick Disease Type C1.
    (patent number 330 EPP0; date filing: 27.03.2016, published as WO 2017/162806 A1) à continued to Europe and US à 17712159.7 (EU)
  • Method for treating non-alcoholic steatohepatitis. (patent number 329 EPP0; date filing: 23.02.2016)
  • Method for the treatment of lysosomal lipid storage diseases. (patent number EP13163419.8; date filing: 11.04.2013)
  • ​Method for treating fatty liver diseases, in particular non-alcoholic steatohepatitis. (patent number WO 2012/019930 A1; date filing: 30.07.2011, international publication date: 16.02.2012)
  • Method for diagnosing fatty liver diseases, in particular non-alcoholic steatohepatits. (patent number EP2418285 A1; date filing: 09.08.2010, international publication date: 15.02.2012). 
  • Method for treating liver inflammation, fibrosis and non-alcoholic steatohepatitis. (patent number EP11155267.5; date filing: 21.02.2011)
  • Phytosterols and phytostanols for the prevention of treatment of inflammation. (patent number 11191776.1-1216, date filing: 02.12.2011)
  • Method for diagnosing of pediatric NASH (patent number EP14188909.7, date filing: 14.10.2014, WO 2016/059054)

Molecular epigenetic mechanisms in development, cancer and metabolism

Gene-environment interactions - molecular epigenetic mechanisms underlying embryogenesis, oncogenesis and metabolic responses. Central to our studies are the molecular links between cell signalling and chromatin structure modulation. Chromatin structure remodeling is a vital aspect of numerous important DNA-templated processes (i.a. transcription, DNA replication, DNA repair, imprinting, X-inactivation) and hence of development and homeostasis. Disruption of chromatin remodelling is at the basis of abnormal development, tumorigenesis and the metabolic syndrome In contrast to (congenic, acquired) genetic abnormalities, abnormal epigenetic control may be responsive to and corrected by changing the cells’ microenvironment (nutrients, oxygen, drugs). Clinical application of epigenetic therapy requires detailed understanding of underlying molecular mechanisms.

Signalling to chromatin; novel interactors of Polycomb Group proteins
The Polycomb Group of regulator complexes play pivotal roles in many chromatin-based processes. Our team produced one of the first molecular connections between cell signalling and chromatin remodelling by Polycomb Group (PcG) proteins: activation of the canonical MAPK pathways activates downstream kinases called MAPKAP-kinases, which we identified as PcG-kinases. We showed MK3 is an integral member of PcG complexes and identified a role for MK3 in a negative feedback mechanism that re-establishes PcG-mediated gene repression. Post-translational modifications control protein interactions, activity and stability. We discovered that MK3 and PcG are functionally connected in proliferative capacity. As MK3 is often lost or over-active in tumors, our findings have a direct bearing on our understanding of abnormal differentiation and proliferation in cancer. Current studies focus on post-translational modification of PcG proteins and their molecular consequence and biological relevance (development, cancer, metabolic responses). These studies are carried out with international collaborators (F Peronnet, Paris, FR; UR Rapp, Münich, GE) and include state-of-the-art omics and molecular genetics approaches.

Tissue regeneration; gene-environment interactions in chondrogenesis
The Molecular Epigenetics (J.W. Voncken) and Orthopaedic Surgery and Research (LW vanRhijn, TJM Welting) teams have jointly identified novel molecular epigenetic connections in the context of early responses in chondrogenic differentiation. We identified an important role for immediate early genes EGR1 and PcG proteins in coordinating proliferation and differentiation during the initial phases of chondrogenic commitment. Our current efforts have focussed on the intervertebral disc (IVD). Disc degeneration poses a substantial socio-economic burden in developed countries and for which no effective therapy is available. To develop cell replacement and tissue regeneration therapy, much improved understanding of cell ontogeny and their molecular interactions with the micro-environment in healthy and diseased tissue is required. We have established unique novel cell lines representing distinct subpopulations in the IVD. These cell lines have yielded novel biomarkers that differ among subpopulations within the central nucleus pulposus and the surrounding annulus fibrosus, and are currently being studied to ultimately improve regeneration strategies.

Microenvironment, epigenetics and stem cells in development and cancer
Epigenetic regulation mediates adaptation to changes in the micro-environment and constitutes a major underlying mechanism in development, maintenance of cellular diversity, phenotypic plasticity and homeostasis. Cancer cells in solid tumors are often exposed to fluctuating oxygen tension resulting from inadequate blood supply due to poorly developed vasculature. Transcriptional changes in hypoxic cancer cells enable cancer cells to survive and adapt to the hypoxic environment. Repeated oxygen deprivation and reoxygenation is thought to promote tumor stem cell properties, metastasis, and poor patient prognosis. The Molecular Genetics (J.W. Voncken) and Tumor Oncology group (B.G. Wouters; Toronto, Canada) have recently discovered that hypoxia exposure increases global histone-trimethylation and induces a bivalent epigenetic state on numerous key regulatory genes. Current studies focus on the functional consequences thereof for normal and abnormal growth and development.

Team leader
Willem Voncken, PhD
w.voncken@maastrichtuniversity.nl

Research group
Vivian E.H. Dahlmans-van Leeuwen (senior expert technician), Peggy Prickaerts, PhD (postdoc; tumor epigenetics), Guus G.H. van den Akker MSc (PhD student; signalling and epigenetics in cartilage), Xiaoqing Zhu MSc (PhD student; epigenetics in metabolic responses), Jolien Vanhove MSc (PhD student, KU Leuven; iPSCs in hepatogenesis), Isabelle Schiffer MSc (PhD student, USC Los Angeles; leukemia research).

Past PhD students: Hanneke Niessen, PhD (molecular epigenetics), Frank Spaapen, PhD (molecular epigenetics), Pieter Emans, PhD (Orthop), Edwin Janssen, PhD (Orthop).
The team hosts local national and international undergraduate students.

School
GROW

  • Cardiac energy metabolism and chronic cardiac disease

  • Inflammation and lipid signaling for novel diagnosis and treatment of metabolic diseases

  • Molecular epigenetic mechanisms in development, cancer and metabolism