Joost J F P Luiken

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (162)595.36 Total impact

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    ABSTRACT: Cardiac glucose utilization is regulated by translocation of the glucose transporter GLUT4 from intracellular stores to the sarcolemma. During lipid-induced insulin resistance, the sarcolemmal presence of the fatty acid transporter CD36 increases, resulting in increased fatty acid uptake and elevation of intracellular lipid metabolites, which interfere with insulin-stimulated GLUT4 translocation, and consequently lead to impaired glucose utilization.
    11/2015; 10(3):128-128. DOI:10.1007/s12467-012-0077-0
  • Joost J.F.P. Luiken · Dietbert Neumann · Jan F.C. Glatz ·
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    ABSTRACT: Glucose uptake by heart and skeletal muscle is regulated by the reversible translocation of the glucose transporter GLUT4 from endosomal stores to the sarcolemma. GLUT4 translocation is known to be induced by both insulin and muscle contraction. Insulin-induced GLUT4 translocation occurs through activation of two separate signaling branches, one involving insulin receptor-substrate- 1, phosphatidylinositol-3 kinase and PKB/Akt, and the other involving Cap, cbl and TC10.
    11/2015; 10(3):127-128. DOI:10.1007/s12467-012-0076-1
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    ABSTRACT: Diabetic cardiomyopathy is associated with Zn deficiency. However, the mechanistical link between these processes is incompletely understood. One of the main causal factors in diabetic cardiomyopathy is chronically elevated long-chain fatty acid (LCFA) uptake via increased flux through CD36, the predominant cardiac sarcolemmal LCFA transporter.
    11/2015; 11(4):191-192. DOI:10.1007/s12467-013-0148-x
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    ABSTRACT: Myocardial glucose and long-chain fatty acid uptake are regulated by specific membrane transport proteins, i.e., GLUT4 and CD36, respectively. Upon hormonal (insulin) or mechanical stimuli (muscle contraction) GLUT4 and CD36 move from endosomal stores to the plasma membrane to facilitate substrate uptake. Contraction-mediated substrate uptake is known to require AMP-dependent protein kinase (AMPK) activation.
    11/2015; 10(3):127-127. DOI:10.1007/s12467-012-0075-2
  • Joost J.F.P. Luiken · Ellen Dirkx · Dietbert Neumann · Jan F.C. Glatz ·
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    ABSTRACT: In the insulin resistant/diabetic skeletal and cardiac muscle glucose uptake is greatly impaired, and cell surface localization of the glucose transporter GLUT4 is diminished. Diabetic muscular dysfunction and cardiomyopathy may be averted by strategies that increase glucose uptake.
    11/2015; 11(4):161-161. DOI:10.1007/s12467-013-0105-8
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    ABSTRACT: Muscle contains various fatty acid transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four transporters to the sarcolemma to enhance fatty acid uptake similarly to glucose uptake stimulation via glucose transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle fatty acid transporter translocation is unknown. In muscle from Akt2-knockout mice, we observed that Akt2 is critically involved in both insulin-induced and contraction-induced fatty acid transport and translocation of fatty acid translocase/CD36 (CD36) and FATP1, but not of translocation of fatty acid-binding protein (FABPpm) and FATP4. Instead, Akt2 mediates intracellular retention of both latter transporters. Collectively, our observations reveal novel complexities in signaling mechanisms regulating the translocation of fatty acid transporters in muscle. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 08/2015; 589(19). DOI:10.1016/j.febslet.2015.08.010 · 3.17 Impact Factor
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    ABSTRACT: The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in fatty acid translocase (FAT/CD36)-mediated fatty acid transport, selected enzymes and/or fatty acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance. We measured, daily (on days 1-7) and/or weekly (for 6 weeks), the diet-induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin-stimulated sarcolemmal GLUT4 and glucose transport. We also examined whether upregulating fatty acid oxidation improved glucose transport in insulin-resistant muscles. Finally, in Cd36-knockout mice, we examined the role of FAT/CD36 in intramyocellular lipid accumulation, insulin sensitivity and diet-induced glucose intolerance. Within 2-3 days, diet-induced increases occurred in insulin, sarcolemmal FAT/CD36 (but not fatty acid binding protein [FABPpm] or fatty acid transporter [FATP]1 or 4), fatty acid transport and intramyocellular triacylglycerol, diacylglycerol and ceramide, independent of enzymatic changes or muscle fatty acid oxidation. Diet-induced increases in mitochondria and mitochondrial fatty acid oxidation and impairments in insulin-stimulated glucose transport and GLUT4 translocation occurred much later (≥21 days). FAT/CD36 ablation impaired insulin-stimulated fatty acid transport and lipid accumulation, improved insulin sensitivity and prevented diet-induced glucose intolerance. Increasing fatty acid oxidation in insulin-resistant muscles improved glucose transport. High-fat feeding rapidly increases intramyocellular lipids (in 2-3 days) via insulin-mediated upregulation of sarcolemmal FAT/CD36 and fatty acid transport. The 16-19 day delay in the onset of insulin resistance suggests that additional mechanisms besides intramyocellular lipids contribute to this pathology.
    Diabetologia 07/2015; 58(10). DOI:10.1007/s00125-015-3691-8 · 6.67 Impact Factor
  • Joost J.F.P. Luiken · Jan F.C. Glatz · Dietbert Neumann ·
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    ABSTRACT: Contraction-induced translocation of glucose transporter type-4 (GLUT4) to the sarcolemma is essential to stimulate cardiac glucose uptake during increased energy demand. As such, this process is a target for therapeutic strategies aiming at increasing glucose uptake in insulin-resistant and/or diabetic hearts. AMP-activated protein kinase (AMPK) and its upstream kinases form part of a signaling axis essential for contraction-induced GLUT4 translocation. Recently, activation of protein kinase-D1 (PKD1) was also shown to be as obligatory for contraction-induced GLUT4 translocation in cardiac muscle. However, contraction-induced PKD1 activation in this context occurs independently from AMPK signaling, suggesting that contraction-induced GLUT4 translocation requires the input of two separate signaling pathways. Necessity for dual input would more tightly couple GLUT4 translocation to stimuli that are inherent to cardiac contraction. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Endocrinology and Metabolism 06/2015; 26(8). DOI:10.1016/j.tem.2015.06.002 · 9.39 Impact Factor
  • Dietbert Neumann · Joost J F P Luiken · Miranda Nabben · Jan F C Glatz ·

    Circulation Research 05/2015; 116(10):e95-6. DOI:10.1161/CIRCRESAHA.115.306463 · 11.02 Impact Factor
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    ABSTRACT: The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure. However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart. This review discusses new insights into metabolic adaptations in heart failure. A particular focus lies on data obtained from mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolic pathway and how these differently affect cardiac function. Based on studies in which these mouse models were exposed to ischemic and non-ischemic heart failure, we discuss whether and when modulations in FA metabolism are protective against heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email:
    Cardiovascular Research 03/2015; 106(2). DOI:10.1093/cvr/cvv105 · 5.94 Impact Factor
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    ABSTRACT: Insulin resistance is an important risk factor for the development of several cardiac pathologies, thus advocating strategies for restoring insulin sensitivity of the heart in these conditions. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), have been shown to improve insulin sensitivity in insulin-sensitive tissues, but their direct effect on insulin signaling and metabolic parameters in the myocardium has not been reported previously. The aim of this study was therefore to examine the ability of EPA and DHA to prevent insulin resistance in isolated rat cardiomyocytes. Primary rat cardiomyocytes were made insulin resistant by 48 h incubation in high insulin (HI) medium. Parallel incubations were supplemented by 200 µM EPA or DHA. Addition of EPA or DHA to the medium prevented the induction of insulin resistance in cardiomyocytes by preserving the phosphorylation state of key proteins in the insulin signaling cascade and by preventing persistent relocation of fatty acid transporter CD36 to the sarcolemma. Only cardiomyocytes incubated in the presence of EPA, however, exhibited improvements in glucose and fatty acid uptake and cell shortening. We conclude that ω-3 PUFAs protect metabolic and functional properties of cardiomyocytes subjected to insulin resistance-evoking conditions. Copyright © 2014, American Journal of Physiology - Cell Physiology.
    AJP Cell Physiology 12/2014; 308(4):ajpcell.00073.2014. DOI:10.1152/ajpcell.00073.2014 · 3.78 Impact Factor
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    ABSTRACT: Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac 31P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo 1H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 10/2014; 1841(10). DOI:10.1016/j.bbalip.2014.07.016 · 5.16 Impact Factor
  • J.J.F.P. Luiken · J.F.C. Glatz ·

    Atherosclerosis 08/2014; 235(2):e301. DOI:10.1016/j.atherosclerosis.2014.05.952 · 3.99 Impact Factor
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    ABSTRACT: Activation of AMP-activated protein kinase (AMPK) in cardiomyocytes induces translocation of glucose transporter GLUT4 and long-chain fatty acid (LCFA) transporter CD36 from endosomal stores to the sarcolemma to enhance glucose and LCFA uptake, respectively. Ca(2+)/calmodulin-activated kinase kinase-β (CaMKKβ) has been positioned directly upstream of AMPK. However, it is unknown whether acute increases in [Ca(2+)]i stimulate translocation of GLUT4 and CD36 and uptake of glucose and LCFA, and whether Ca(2+) signaling converges with AMPK signaling to exert these actions. Therefore, we studied the interplay between Ca(2+) and AMPK signaling in regulation of cardiomyocyte substrate uptake. Exposure of primary cardiomyocytes to inhibitors or activators of Ca(2+) signaling neither affected AMPK-Thr172 phosphorylation nor basal and AMPK-mediated glucose and LCFA uptake. Despite their lack of an effect on substrate uptake, Ca(2+) signaling activators induced GLUT4 and CD36 translocation. In contrast, AMPK activators stimulated GLUT4/CD36 translocation as well as glucose/LCFA uptake. When cardiomyocytes were co-treated with Ca(2+) signaling and AMPK activators, Ca(2+) signaling activators further enhanced AMPK-induced glucose/LCFA uptake. In conclusion, Ca(2+) signaling shows no involvement in AMPK-induced GLUT4/CD36 translocation and substrate uptake, but elicits transporter translocation via a separate pathway requiring CaMKKβ/CaMKs. Ca(2+)-induced transporter translocation by itself appears ineffective to increase substrate uptake, but requires additional AMPK activation to effectuate transporter translocation into increased substrate uptake. Ca(2+)-induced transporter translocation might be crucial under excessive cardiac stress conditions that require supraphysiological energy demands. Alternatively, Ca(2+) signaling might prepare the heart for substrate uptake during physiological contraction by inducing transporter translocation.
    AJP Endocrinology and Metabolism 06/2014; 307(2). DOI:10.1152/ajpendo.00655.2013 · 3.79 Impact Factor
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    Diabetologie und Stoffwechsel 05/2014; 9(S 01). DOI:10.1055/s-0034-1375098 · 0.33 Impact Factor
  • Jan F. C. Glatz · Joost J. F. P. Luiken ·
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    ABSTRACT: Fatty acids not only are important metabolic substrates and building blocks of lipids but are increasingly being recognized for their modulatory roles in a wide variety of cellular processes including gene expression, together referred to as the ‘message-modulator’ function of fatty acids. Crucial for this latter role is the bioavailability of fatty acids, which is governed by their interaction with soluble proteins capable of binding fatty acids, i.e., plasma albumin and cytoplasmic fatty acid-binding protein (FABPc), and with both the lipid and protein components of biological membranes, including membrane-associated fatty acid-binding proteins such as the transmembrane protein CD36. Manipulating fatty acid availability holds promise as therapeutic approach for chronic diseases that are characterized by a perturbed fatty acid metabolism.
    Prostaglandins Leukotrienes and Essential Fatty Acids 03/2014; 92. DOI:10.1016/j.plefa.2014.02.007 · 2.35 Impact Factor
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    ABSTRACT: Abstract Stimulation of cellular fatty acid uptake by induction of insulin signalling or AMP-kinase (AMPK) activation is due to translocation of the fatty acid-transporter CD36 from intracellular stores to the plasma membrane (PM). For investigating the role of the four Cys-residues within CD36's cytoplasmic tails in CD36 translocation, we constructed CHO-cells expressing CD36 mutants in which all four, two, or one of the intracellular Cys were replaced by Ser. Intracellular and PM localization of all mutants was similar to wild-type CD36 (CD36wt). Hence, the four Cys do not regulate sub-cellular CD36 localization. However, in contrast to CD36wt, insulin or AMPK activation failed to induce translocation of any of the mutants, indicating that all four intracellular Cys residues are essential for CD36 translocation. The mechanism of defective translocation of mutant CD36 is unknown, but appears not due to loss of S-palmitoylation of the cytoplasmic tails or to aberrant oligomerization of the mutants.
    Archives of Physiology and Biochemistry 02/2014; 120(1):40-9. DOI:10.3109/13813455.2013.876049. · 1.76 Impact Factor
  • Jan F. C. Glatz · Joost J. F. P. Luiken ·
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    ABSTRACT: Carbohydrates and long-chain fatty acids are the predominant substrates for cardiac energy production. While the mechanism and regulation of myocardial carbohydrate (glucose, lactate) uptake have been unraveled in detail in the 1990s, insight into fatty acid uptake originates from more recent studies. Fatty acid movement across the sarcolemma is facilitated by membrane-associated proteins, specifically CD36, membrane-associated fatty acid-binding protein (FABPpm) and selected fatty acid transport protein (FATP) isoforms, and is up- or downregulated through changes in sarcolemmal content of (primarily) CD36. The recruitment of CD36 from an endosomal storage pool to the sarcolemma, which is under the control of various physiological stimuli (including insulin and contraction), represents a pivotal step in the overall regulation of myocardial fatty acid uptake and utilization. Dysregulation of the intracellular cycling of CD36 underlies various cardiac metabolic diseases. As a result, the mechanism and regulation of myocardial glucose uptake by GLUT4 cycling and of fatty acid uptake by CD36 cycling are very similar. Likely, manipulation of the presence and/or activity of substrate transporters for glucose and fatty acids in the sarcolemma holds promise as therapeutic approach to alter cardiac substrate preference in disease so as to regain metabolic homeostasis and rectify cardiac functioning.
    Cardiac Energy Metabolism in Health and Disease, 01/2014: pages 49-67; , ISBN: 978-1-4939-1226-1
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    ABSTRACT: -Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to acutely regulate substrate metabolism. We hypothesised that, during ischemia, fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma, to limit fatty acid uptake when fatty acid oxidation is inhibited. -Wistar rat hearts were perfused during pre-ischemia, low-flow ischemia and reperfusion, using (3)H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to pre-ischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion, in contrast, glycolytic rates decreased to 30% of pre-ischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content. -During ischemia FAT/CD36 moved away from the sarcolemma as GLUT4 moved towards the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, whilst intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels.
    Circulation Heart Failure 08/2013; 6(5). DOI:10.1161/CIRCHEARTFAILURE.112.000342 · 5.89 Impact Factor
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    Dataset: E618.full

Publication Stats

7k Citations
595.36 Total Impact Points


  • 1998-2015
    • Maastricht University
      • • Department of Genetics & Cell Biology
      • • Department of Genetics and Molecular Cell Biology
      • • Department of Physiology
      Maestricht, Limburg, Netherlands
  • 2012
    • German Diabetes Center
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2004-2012
    • University of Guelph
      • Department of Human Health and Nutritional Sciences (HHNS)
      Guelph, Ontario, Canada
  • 2011
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
  • 2005-2008
    • Universiteit Utrecht
      • Division of Endocrinology and Metabolism
      Utrecht, Utrecht, Netherlands
  • 1998-2004
    • University of Waterloo
      • Department of Kinesiology
      Waterloo, Quebec, Canada
  • 1994-1997
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands