38 results on '"Glatz, Jan F.C."'
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2. CD36 as a target for metabolic modulation therapy in cardiac disease
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Glatz, Jan F.C., Wang, Fang, Nabben, Miranda, and Luiken, Joost J.F.P.
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ABSTRACTIntroduction: Disturbances in myocardial lipid metabolism are increasingly being recognized as drivers of the development and progression of heart disease. Therefore, there is a need for treatments that can directly target lipid metabolic defects in heart failure. The membrane-associated glycoprotein CD36 plays a pivotal role in governing myocardial lipid metabolism by mediating lipid signaling and facilitating the cellular uptake of long-chain fatty acids. Emerging evidence suggests that CD36 is a prominent target in the treatment of heart failure.Areas covered: This article provides an overview of the key role of CD36 for proper contractile functioning of a healthy heart, its implications in the development of cardiac disease (ischemia/reperfusion, cardiac hypertrophy, and diabetic cardiomyopathy), and its application as a target to normalize cardiac metabolism as part of so-called metabolic modulation therapy.Expert opinion: CD36 appears a promising and effective therapeutic target in the treatment of heart failure. Natural compounds and chemical agents known to alter the amount or subcellular distribution of CD36 or inhibit its functioning, should be evaluated for their potency to correct cardiac metabolism and cure heart disease.
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- 2021
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3. Metabolic Profiling Associates with Disease Severity in Nonischemic Dilated Cardiomyopathy.
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Verdonschot, Job A.J., Wang, Ping, Van Bilsen, Marc, Hazebroek, Mark R., Merken, Jort J., Vanhoutte, Els K., Henkens, Michiel T.H.M., Van Den Wijngaard, Arthur, Glatz, Jan F.C., Krapels, Ingrid P.C., Brunner, Han G., Heymans, Stephane R.B., and Bierau, Jörgen
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Background: Metabolomic profiling may have diagnostic and prognostic value in heart failure. This study investigated whether targeted blood and urine metabolomics reflects disease severity in patients with nonischemic dilated cardiomyopathy (DCM) and compared its incremental value on top of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).Methods and Results: A total of 149 metabolites were measured in plasma and urine samples of 273 patients with DCM and with varying stages of disease (patients with DCM and normal left ventricular reverse remodeling, n = 70; asymptomatic DCM, n = 72; and symptomatic DCM, n = 131). Acylcarnitines, sialic acid and glutamic acid are the most distinctive metabolites associated with disease severity, as repeatedly revealed by unibiomarker linear regression, sparse partial least squares discriminant analysis, random forest, and conditional random forest analyses. However, the absolute difference in the metabolic profile among groups was marginal. A decision-tree model based on the top metabolites did not surpass NT-proBNP in classifying stages. However, a combination of NT-proBNP and the top metabolites improved the decision tree to distinguish patients with DCM and left ventricular reverse remodeling from symptomatic DCM (area under the curve 0.813 ± 0.138 vs 0.739 ± 0.114; P = 0.02).Conclusion: Functional cardiac recovery is reflected in metabolomics. These alterations reveal potential alternative treatment targets in advanced symptomatic DCM. The metabolic profile can complement NT-proBNP in determining disease severity in nonischemic DCM. [ABSTRACT FROM AUTHOR]- Published
- 2020
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4. Time for a détente in the war on the mechanism of cellular fatty acid uptake
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Glatz, Jan F.C. and Luiken, Joost J.F.P.
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- 2020
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5. The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target.
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Chanda, Dipanjan, Neumann, Dietbert, and Glatz, Jan F.C.
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Highlights • The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators with a short life span that exert paracrine or autocrine signaling. • The endocannabinoid system is a ubiquitous cell signaling system that serves various protective roles in pathophysiological conditions. • Modulation of the endocannabinoid system may be an effective approach to alter cellular metabolism. Abstract The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators that exert protective roles in pathophysiological conditions, including cardiovascular diseases. In this brief review, we provide a conceptual framework linking endocannabinoid signaling to the control of the cellular and molecular hallmarks, and categorize the key components of endocannabinoid signaling that may serve as targets for novel therapeutics. The emerging picture not only reinforces endocannabinoids as potent regulators of cellular metabolism but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Lipids and lipid binding proteins: A perfect match.
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Glatz, Jan F.C.
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Lipids serve a great variety of functions, ranging from structural components of biological membranes to signaling molecules affecting various cellular functions. Several of these functions are related to the unique physico-chemical properties shared by all lipid species, i.e., their hydrophobicity. The latter, however, is accompanied by a poor solubility in an aqueous environment and thus a severe limitation in the transport of lipids in aqueous compartments such as blood plasma and the cellular soluble cytoplasm. Specific proteins which can reversibly and non-covalently associate with lipids, designated as lipid binding proteins or lipid chaperones, greatly enhance the aqueous solubility of lipids and facilitate their transport between tissues and within tissue cells. Importantly, transport of lipids across biological membranes also is facilitated by specific (membrane-associated) lipid binding proteins. Together, these lipid binding proteins determine the bio-availability of their ligands, and thereby markedly influence the subsequent processing, utilization, or signaling effect of lipids. The bio-availability of specific lipid species thus is governed by the presence of specific lipid binding proteins, the affinity of these proteins for distinct lipid species, and the presence of competing ligands (including pharmaceutical compounds). Recent studies suggest that post-translational modifications of lipid binding proteins may have great impact on lipid–protein interactions. As a result, several levels of regulation exist that together determine the bio-availability of lipid species. This short review discusses the significance of lipid binding proteins and their potential application as targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]
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- 2015
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7. Fatty acids in cell signaling: Historical perspective and future outlook.
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Glatz, Jan F.C. and Luiken, Joost J.F.P.
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Fatty acids are not only important metabolic substrates and building blocks of lipids but are also 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 (FABP c ), 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. [ABSTRACT FROM AUTHOR]
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- 2015
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8. CD36 as a target to prevent cardiac lipotoxicity and insulin resistance.
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Glatz, Jan F.C., Angin, Yeliz, Steinbusch, Laura K.M., Schwenk, Robert W., and Luiken, Joost J.F.P.
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INSULIN resistance ,MEMBRANE proteins ,CARDIOVASCULAR diseases ,FATTY acid-binding proteins ,SCAVENGER receptors (Biochemistry) ,TYPE 2 diabetes prevention ,CELL membranes ,TRIGLYCERIDES ,METABOLIC disorders - Abstract
Abstract: The fatty acid transporter and scavenger receptor CD36 is increasingly being implicated in the pathogenesis of insulin resistance and its progression towards type 2 diabetes and associated cardiovascular complications. The redistribution of CD36 from intracellular stores to the plasma membrane is one of the earliest changes occurring in the heart during diet induced obesity and insulin resistance. This elicits an increased rate of fatty acid uptake and enhanced incorporation into triacylglycerol stores and lipid intermediates to subsequently interfere with insulin-induced GLUT4 recruitment (i.e., insulin resistance). In the present paper we discuss the potential of CD36 to serve as a target to rectify abnormal myocardial fatty acid uptake rates in cardiac lipotoxic diseases. Two approaches are described: (i) immunochemical inhibition of CD36 present at the sarcolemma and (ii) interference with the subcellular recycling of CD36. Using in vitro model systems of high-fat diet induced insulin resistance, the results indicate the feasibility of using CD36 as a target for adaptation of cardiac metabolic substrate utilization. In conclusion, CD36 deserves further attention as a promising therapeutic target to redirect fatty acid fluxes in the body. [Copyright &y& Elsevier]
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- 2013
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9. High fat diet induced diabetic cardiomyopathy.
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Dirkx, Ellen, Schwenk, Robert W., Glatz, Jan F.C., Luiken, Joost J.F.P., and van Eys, Guillaume J.J.M.
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CARDIOMYOPATHIES ,DIETARY fats ,GLUCOSE ,REACTIVE oxygen species ,DIGLYCERIDES ,PEROXISOMES ,GENE expression - Abstract
Abstract: In response to a chronic high plasma concentration of long-chain fatty acids (FAs), the heart is forced to increase the uptake of FA at the cost of glucose. This switch in metabolic substrate uptake is accompanied by an increased presence of the FA transporter CD36 at the cardiac plasma membrane and over time results in the development of cardiac insulin resistance and ultimately diabetic cardiomyopathy. FA can interact with peroxisome proliferator-activated receptors (PPARs), which induce upregulation of the expression of enzymes necessary for their disposal through mitochondrial β-oxidation, but also stimulate FA uptake. This then leads to a further increase in FA concentration in the cytoplasm of cardiomyocytes. These metabolic changes are supposed to play an important role in the development of cardiomyopathy. Although the onset of this pathology is an increased FA utilization by the heart, the subsequent lipid overload results in an increased production of reactive oxygen species (ROS) and accumulation of lipid intermediates such as diacylglycerols (DAG) and ceramide. These compounds have a profound impact on signaling pathways, in particular insulin signaling. Over time the metabolic changes will introduce structural changes that affect cardiac contractile characteristics. The present mini-review will focus on the lipid-induced changes that link metabolic perturbation, characteristic for type 2 diabetes, with cardiac remodeling and dysfunction. [Copyright &y& Elsevier]
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- 2011
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10. Fatty acid transport across the cell membrane: Regulation by fatty acid transporters.
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Schwenk, Robert W., Holloway, Graham P., Luiken, Joost J.F.P., Bonen, Arend, and Glatz, Jan F.C.
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CELL membranes ,FATTY acid-binding proteins ,HOMEOSTASIS ,ACYLTRANSFERASES ,METABOLIC disorders ,INSULIN resistance ,MEMBRANE proteins ,ENZYME activation - Abstract
Abstract: Transport of long-chain fatty acids across the cell membrane has long been thought to occur by passive diffusion. However, in recent years there has been a fundamental shift in understanding, and it is now generally recognized that fatty acids cross the cell membrane via a protein-mediated mechanism. Membrane-associated fatty acid-binding proteins (‘fatty acid transporters’) not only facilitate but also regulate cellular fatty acid uptake, for instance through their inducible rapid (and reversible) translocation from intracellular storage pools to the cell membrane. A number of fatty acid transporters have been identified, including CD36, plasma membrane-associated fatty acid-binding protein (FABP
pm ), and a family of fatty acid transport proteins (FATP1–6). Fatty acid transporters are also implicated in metabolic disease, such as insulin resistance and type-2 diabetes. In this report we briefly review current understanding of the mechanism of transmembrane fatty acid transport, and the function of fatty acid transporters in healthy cardiac and skeletal muscle, and in insulin resistance/type-2 diabetes. Fatty acid transporters hold promise as a future target to rectify lipid fluxes in the body and regain metabolic homeostasis. [Copyright &y& Elsevier]- Published
- 2010
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11. Specific amino acid supplementation rescues the heart from lipid overload-induced insulin resistance and contractile dysfunction by targeting the endosomal mTOR–v-ATPase axis.
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Wang, Shujin, Schianchi, Francesco, Neumann, Dietbert, Wong, Li-Yen, Sun, Aomin, van Nieuwenhoven, Frans A., Zeegers, Maurice P., Strzelecka, Agnieszka, Col, Umare, Glatz, Jan F.C., Nabben, Miranda, and Luiken, Joost J.F.P.
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The diabetic heart is characterized by extensive lipid accumulation which often leads to cardiac contractile dysfunction. The underlying mechanism involves a pivotal role for vacuolar-type H
+ -ATPase (v-ATPase, functioning as endosomal/lysosomal proton pump). Specifically, lipid oversupply to the heart causes disassembly of v-ATPase and endosomal deacidification. Endosomes are storage compartments for lipid transporter CD36. However, upon endosomal deacidification, CD36 is expelled to translocate to the sarcolemma, thereby inducing myocardial lipid accumulation, insulin resistance, and contractile dysfunction. Hence, the v-ATPase assembly may be a suitable target for ameliorating diabetic cardiomyopathy. Another function of v-ATPase involves the binding of anabolic master-regulator mTORC1 to endosomes, a prerequisite for the activation of mTORC1 by amino acids (AAs). We examined whether the relationship between v-ATPase and mTORC1 also operates reciprocally; specifically, whether AA induces v-ATPase reassembly in a mTORC1-dependent manner to prevent excess lipids from entering and damaging the heart. Lipid overexposed rodent/human cardiomyocytes and high-fat diet-fed rats were treated with a specific cocktail of AAs (lysine/leucine/arginine). Then, v-ATPase assembly status/activity, cell surface CD36 content, myocellular lipid uptake/accumulation, insulin sensitivity, and contractile function were measured. To elucidate underlying mechanisms, specific gene knockdown was employed, followed by subcellular fractionation, and coimmunoprecipitation. In lipid-overexposed cardiomyocytes, lysine/leucine/arginine reinternalized CD36 to the endosomes, prevented/reversed lipid accumulation, preserved/restored insulin sensitivity, and contractile function. These beneficial AA actions required the mTORC1–v-ATPase axis, adaptor protein Ragulator, and endosomal/lysosomal AA transporter SLC38A9, indicating an endosome-centric inside-out AA sensing mechanism. In high-fat diet-fed rats, lysine/leucine/arginine had similar beneficial actions at the myocellular level as in vitro in lipid-overexposed cardiomyocytes and partially reversed cardiac hypertrophy. Specific AAs acting through v-ATPase reassembly reduce cardiac lipid uptake raising the possibility for treatment in situations of lipid overload and associated insulin resistance. [Display omitted] • High physiological concentrations of specific AAs (K/L/R) activate v-ATPase. • The KLR mix activates v-ATPase by mutually dependent activation of mTORC1. • KLR-induced v-ATPase activation enables endosomes to retain lipid transporter CD36. • KLR mends lipid-induced insulin resistance and cardiomyocytic contractile dysfunction. • KLR reverses v-ATPase disassembly and cardiac hypertrophy in high-fat diet-fed rats. [ABSTRACT FROM AUTHOR]- Published
- 2021
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12. Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane.
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Chabowski, Adrian, Górski, Jan, Luiken, Joost J.F.P., Glatz, Jan F.C., and Bonen, Arend
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FATTY acids ,BLOOD plasma ,HORMONES ,HYPOGLYCEMIC agents - Abstract
Abstract: There is substantial molecular, biochemical and physiologic evidence that long-chain fatty acid transport involves a protein-mediated process. A number of fatty acid transport proteins have been identified, and for unknown reasons, some of these are co-expressed in the same tissues. In muscle and heart FAT/CD36 and FABPpm appear to be key transporters. Both proteins are regulated acutely (within minutes) and chronically (hours to days) by selected physiologic stimuli (insulin, AMP kinase activation). Acute regulation involves the translocation of FAT/CD36 by insulin, muscle contraction and AMP kinase activation, while FABPpm is induced to translocate by muscle contraction and AMP kinase activation, but not by insulin. Protein expression of FAT/CD36 and FABPpm is regulated by prolonged AMP kinase activation (heart) or increased muscle contraction. Prolonged insulin exposure increases the expression of FAT/CD36 but not FABPpm. Trafficking of fatty acid transporters between an intracellular compartment(s) and the plasma membrane is altered in insulin-resistant skeletal muscle, as some FAT/CD36 is permanently relocated to plasma membrane, thereby contributing to insulin resistance due to the increased influx of fatty acids into muscle cells. Studies in FAT/CD36 null mice have revealed that this transporter is key to regulating the increase in the rate of fatty acid metabolism in heart and skeletal muscle. It appears based on a number of experiments that FAT/CD36 and FABPpm may collaborate to increase the rates of fatty acid transport, as these proteins co-immunoprecipitate. [Copyright &y& Elsevier]
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- 2007
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13. FAT/CD36 expression is not ablated in spontaneously hypertensive rats
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Bonen, Arend, Han, Xiao-Xia, Tandon, Narendra N., Glatz, Jan F.C., Lally, James, Snook, Laelie A., and Luiken, Joost J. F.P.
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There is doubt whether spontaneously hypertensive rats (SHR; North American strain) are null for fatty acid translocase (FAT/CD36). Therefore, we examined whether FAT/CD36 is expressed in heart, muscle, liver and adipose tissue in SHR. Insulin resistance was present in SHR skeletal muscle. We confirmed that SHR expressed aberrant FAT mRNAs in key metabolic tissues; namely, the major 2.9 kb transcript was not expressed, but 3.8 and 5.4 kb transcripts were present. Despite this, FAT/CD36 protein was expressed in all tissues, although there were tissue-specific reductions in FAT/CD36 protein expression and plasmalemmal content, ranging from 26–85%. Fatty acid transport was reduced in adipose tissue (−50%) and was increased in liver (+47%). Normal rates of fatty acid transport occurred in heart and muscle, possibly due to compensatory upregulation of plasmalemmal fatty acid binding protein (FABPpm) in red (+123%) and white muscle (+110%). In conclusion, SHRs (North American strain) are not a natural FAT/CD36 null model, the North American strain of SHR express FAT/CD36, albeit at reduced levels.
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- 2009
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14. New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36
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BRINKMANN, Joep F.F., ABUMRAD, Nada A., IBRAHIMI, Azeddine, vanderVUSSE, Ger J., and GLATZ, Jan F.C.
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Long-chain fatty acids are an important source of energy for several cell types, in particular for the heart muscle cell. Three different proteins, fatty acid translocase (FAT)/CD36, fatty acid transport protein and plasma membrane fatty acid binding protein, have been identified as possible membrane fatty acid transporters. Much information has been accumulated recently about the fatty acid transporting function of FAT/CD36. Several experimental models to study the influence of altered FAT/CD36 expression on fatty acid homoeostasis have been identified or developed, and underscore the importance of FAT/CD36 for adequate fatty acid transport. These models include the FAT/CD36 null mouse, the spontaneously hypertensive rat and FAT/CD36-deficient humans. The fatty acid transporting role of FAT/CD36 is further demonstrated in mice overexpressing muscle-specific FAT/CD36, and in transgenic mice generated using a genetic-rescue approach. In addition, a wealth of information has been gathered about the mechanisms that regulate FAT/CD36 gene expression and the presence of functional FAT/CD36 on the plasma membrane. Available data also indicate that FAT/CD36 may have an important role in the aetiology of cardiac disease, especially cardiac hypertrophy and diabetic cardiomyopathy. This review discusses our current knowledge of the three candidate fatty acid transporters, the metabolic consequences of alterations in FAT/CD36 levels in different models, and the mechanisms that have been identified for FAT/CD36 regulation.
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- 2002
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15. Exercise and insulin increase muscle fatty acid uptake by recruiting putative fatty acid transporters to the sarcolemma
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Glatz, Jan F.C., Bonen, Arend, and Luiken, Joost J.F.P.
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Skeletal muscle metabolic energy, needed to maintain contractile activity, is mainly obtained from glucose and long-chain fatty acids. Recent studies have revealed a remarkable parallel between the regulation of uptake of glucose and fatty acids by muscle, in that each is mediated by sarcolemmal transporters that are recruited from an intracellular storage site. The focus of this review is to describe newly obtained insights on the recruitment of fatty acid transporters and their malfunctioning in diabetes.
- Published
- 2002
16. Chronic Leptin Administration Decreases Fatty Acid Uptake and Fatty Acid Transporters in Rat Skeletal Muscle*
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Steinberg, Gregory R., Dyck, David J., Calles-Escandon, Jorges, Tandon, Narendra N., Luiken, Joost J.F.P., Glatz, Jan F.C., and Bonen, Arend
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Chronic leptin administration reduces triacylglycerol content in skeletal muscle. We hypothesized that chronic leptin treatment, within physiologic limits, would reduce the fatty acid uptake capacity of red and white skeletal muscle due to a reduction in transport protein expression (fatty acid translocase (FAT/CD36) and plasma membrane-associated fatty acid-binding protein (FABPpm)) at the plasma membrane. Female Sprague-Dawley rats were infused for 2 weeks with leptin (0.5 mg/kg/day) using subcutaneously implanted miniosmotic pumps. Control and pair-fed animals received saline-filled implants. Leptin levels were significantly elevated (∼4-fold; p< 0.001) in treated animals, whereas pair-fed treated animals had reduced serum leptin levels (approximately −2-fold; p< 0.01) relative to controls. Palmitate transport rates into giant sarcolemmal vesicles were reduced following leptin treatment in both red (−45%) and white (−84%) skeletal muscle compared with control and pair-fed animals (p< 0.05). Leptin treatment reduced FAT mRNA (red, −70%,p< 0.001; white, −48%, p< 0.01) and FAT/CD36 protein expression (red, −32%; p< 0.05) in whole muscle homogenates, whereas FABPpm mRNA and protein expression were unaltered. However, in leptin-treated animals plasma membrane fractions of both FAT/CD36 and FABPpm protein expression were significantly reduced in red (−28 and −34%, respectively) and white (−44 and −56%, respectively) muscles (p< 0.05). Across all experimental treatments and muscles, palmitate uptake by giant sarcolemmal vesicles was highly correlated with the plasma membrane FAT/CD36 protein (r= 0.88,p< 0.01) and plasma membrane FABPpm protein (r= 0.94, p< 0.01). These studies provide the first evidence that protein-mediated long chain fatty acid transport is subject to long term regulation by leptin.
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- 2002
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17. Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats*
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Luiken, Joost J.F.P., Arumugam, Yoga, Dyck, David J., Bell, Rhonda C., Pelsers, Maurice M.L., Turcotte, Lorraine P., Tandon, Narendra N., Glatz, Jan F.C., and Bonen, Arend
- Abstract
Giant vesicles were used to study the rates of uptake of long-chain fatty acids by heart, skeletal muscle, and adipose tissue of obese and lean Zucker rats. With obesity there was an increase in vesicular fatty acid uptake of 1.8-fold in heart, muscle and adipose tissue. In some tissues only fatty acid translocase (FAT) mRNA (heart, +37%; adipose, +80%) and fatty acid-binding protein (FABPpm) mRNA (heart, +148%; adipose, +196%) were increased. At the protein level FABPpm expression was not changed in any tissues except muscle (+14%), and FAT/CD36 protein content was altered slightly in adipose tissue (+26%). In marked contrast, the plasma membrane FAT/CD36 protein was increased in heart (+60%), muscle (+80%), and adipose tissue (+50%). The plasma membrane FABPpm was altered only in heart (+50%) and adipose tissues (+70%). Thus, in obesity, alterations in fatty acid transport in metabolically important tissues are not associated with changes in fatty acid transporter mRNAs or altered fatty acid transport protein expression but with their increased abundance at the plasma membrane. We speculate that in obesity fatty acid transporters are relocated from an intracellular pool to the plasma membrane in heart, muscle, and adipose tissues.
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- 2001
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18. Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart
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Van der Lee, Karin A.J.M., Willemsen, Peter H.M., Samec, Sonia, Seydoux, Josiane, Dulloo, Abdul G., Pelsers, Maurice M.A.L., Glatz, Jan F.C., Van der Vusse, Ger J., and Van Bilsen, Marc
- Abstract
During fasting, when overall metabolism changes, the contribution of glucose and fatty acids (FA) to cardiac energy production alters as well. Here, we examined if the heart is able to adapt to such fasting-induced changes by modulation of its gene expression. Rats were fed ad libitumor fasted for 46 h, resulting in reduced circulating glucose levels and a 3-fold rise in FA. Besides changes in the cardiac activity or content of proteins involved in glucose or FA metabolism, mRNA levels also altered. The cardiac expression of genes coding for glucose-handling proteins (glucose transporter GLUT4, hexokinase I and II) was up to 70% lower in fasted than in fed rats. In contrast, the mRNA levels of various genes involved in FA transport and metabolism (FA translocase/CD36, muscle-type carnitine palmitoyl transferase 1, long-chain acyl-CoA dehydrogenase) and of the uncoupling protein UCP-3 increased over 50% in hearts of fasted rats. Surprisingly, mRNA levels of the fatty acid-activated transcription factors PPARα and PPARβ/δ were reduced in hearts of fasted rats, whereas in livers, fasting led to a marked rise in PPARα mRNA. Reducing FA levels by nicotinic acid administration during the final 8 h of fasting did not affect the expression of the majority of metabolic genes, but totally abolished the induction of UCP-3. In conclusion, the adult rat heart responds to changes in nutritional status, as provoked by 46 h fasting, through adjustment of glucose as well as FA metabolism at the level of gene expression.
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- 2001
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19. Unravelling the significance of cellular fatty acid-binding proteins
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Glatz, Jan F.C. and Storch, Judith
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Cellular long-chain fatty acid (FA) transport and metabolism are believed to be regulated by membrane-associated and soluble proteins that bind and transport FAs. Several different classes of membrane proteins have been proposed as FA acceptors or transmembrane FA transporters. New evidence from in-vitro and whole-animal studies supports the existence of protein-mediated transmembrane transport of FAs, which is likely to coexist with passive diffusional uptake. The trafficking of FAs by intracellular fatty acid-binding proteins may involve their interaction with specific membrane or protein targets. Evidence is also emerging for concerted actions between the membrane and cytoplasmic fatty acid-binding proteins that allow for efficient regulation of FA transport and metabolism.
- Published
- 2001
20. Acute Regulation of Fatty Acid Uptake Involves the Cellular Redistribution of Fatty Acid Translocase*
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Bonen, Arend, Luiken, Joost J. F.P., Arumugam, Yoga, Glatz, Jan F.C., and Tandon, Narendra N.
- Abstract
We used muscle contraction, which increases fatty acid oxidation, as a model to determine whether fatty acid transport is acutely regulated by fatty acid translocase (FAT/CD36). Palmitate uptake by giant vesicles, obtained from skeletal muscle, was increased by muscle contraction. Kinetic studies indicated that muscle contraction increased Vmax, butKmremained unaltered. Sulfo-N-succinimidyl oleate, a specific inhibitor of FAT/CD36, fully blocked the contraction-induced increase in palmitate uptake. In giant vesicles from contracting muscles, plasma membrane FAT/CD36 was also increased in parallel with the increase in long chain fatty acid uptake. Further studies showed that like GLUT-4, FAT/CD36 is located in both the plasma membrane and intracellularly (endosomally). With muscle contraction, FAT/CD36 at the surface of the muscle was increased, while concomitantly, FAT/CD36 in the intracellular pool was reduced. Similar responses were observed for GLUT-4. We conclude that fatty acid uptake is subject to short term regulation by muscle contraction and involves the translocation of FAT/CD36 from intracellular stores to the sarcolemma, analogous to the regulation of glucose uptake by GLUT-4.
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- 2000
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21. Comparison of human and rodent cell models to study myocardial lipid-induced insulin resistance.
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Wong, Li-yen, Glatz, Jan F.C., Wang, Shujin, Geraets, Ilvy M.E., Vanherle, Sabina, Wijngaard, Arthur van den, Brunner, Han, Luiken, Joost J.F.P., and Nabben, Miranda
- Abstract
• Human and rodent cardiomyocyte models (hESC-CMs, hiPSC-CMs, HL-1, aRCMs) were compared for their metabolic characteristics. • The four models show similar fatty acid and glucose uptake rates and a similar response to insulin. • Lipid-induced insulin resistance can equally well be triggered in rodent cardiomyocytes and in hESC-CMs and hiPSC-CMs. • hiPSC-CMs are a promising cell model to evaluate the functional consequences of gene variants of unknown significance. Isolated or cultured cells have proven to be valuable model systems to investigate cellular (patho)biology and for screening of the efficacy of drugs or their possible side-effects. Pluripotent stem cells (PSC) can be readily obtained from healthy individuals as well as from diseased patients, and protocols have been developed to differentiate these cells into cardiomyocytes. Hence, these cellular models are moving center stage for a broader application. In this review, we focus on comparing mouse HL-1 cardiomyocytes, isolated adult rat cardiomyocytes, human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for the study of metabolic aspects of cardiac functioning in health and disease. Various studies have reported that these cellular models are suitable for assessing substrate uptake and utilization, in that each display an adequate and similar response to physiological triggers, in particular the presence of insulin. Likewise, disease conditions, such as excess lipid supply, similarly affect each of these rodent and human cardiomyocyte models. It is concluded that PSC-CMs obtained from patients with cardiogenetic abnormalities are promising models to evaluate the functional consequence of gene variants with unknown significance. [ABSTRACT FROM AUTHOR]
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- 2021
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22. Co-expression in rat heart and skeletal muscle of four genes coding for proteins implicated in long-chain fatty acid uptake
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Van Nieuwenhoven, Frans A, Willemsen, Peter H.M, Van der Vusse, Ger J, and Glatz, Jan F.C
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It has been suggested that specific membrane-associated and cytoplasmic proteins cooperate in the uptake of long-chain fatty acids by cardiac and skeletal muscle cells. A prerequisite for this hypothesis would be the co-occurrence of these proteins in muscle. Thus, we studied the possible co-expression in rat muscles of the genes coding for the integral membrane proteins fatty acid transport protein (FATP) and fatty acid translocase (FAT), the membrane-associated plasmalemmal fatty acid-binding protein (FABPpm) and the cytoplasmic heart-type fatty acid-binding protein (H-FABPc). The transcripts of the four proteins were assessed in heart and skeletal muscles of adult Wistar rats, in isolated cells and cell lines from rat heart and also in rat heart during development and upon streptozotocin-induced diabetes. All four genes showed high expression levels in heart, somewhat lower in red skeletal muscle (soleus) and appreciably lower in white skeletal muscle (extensor digitorum longus). FATP, FAT and H-FABPcshowed a 3- to 5-fold increase in mRNA expression during maturational growth of the heart, while the FABPpmexpression remained virtually constant. In the heart, streptozotocin-diabetes induced a slight, but statistically not significant, increase in the expression of all four genes. In conclusion, this study shows the co-expression of FATP, FAT, FABPpmand H-FABPcin rat muscles. This finding supports the possible cooperation of these proteins in the uptake of long-chain fatty acids by muscle cells.
- Published
- 1999
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23. A New Principle for Rapid Immunoassay of Proteins Based on In Situ Precipitate-Enhanced Ellipsometry
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Robers, Markus, Rensink, Irma J.A.M., Hack, C. Erik, Aarden, Lucien A., Reutelingsperger, Chris P.M., Glatz, Jan F.C., and Hermens, Wim Th.
- Abstract
A new technique is presented that allows measurement of protein concentrations in the picomolar range with an assay time of only 10–20min. The method is an enzyme-linked immunosorbent assay (ELISA), but uses in-situ ellipsometric measurement of a precipitating enzyme product instead of the usual colorimetric detection of accumulating enzyme product in solution. Quantitative validation was obtained by use of annexin V, a protein with high binding affinity for phosphatidylserine-containing phospholipid membranes, resulting in a transport-limited adsorption rate. This property was exploited to obtain a range of low surface concentrations of annexin V by timed exposures of phospholipid bilayers to known concentrations of annexin V. Using polyvinylchloride (PVC)-coated and silanized silicon slides, various versions of this technique were used for the rapid assay of fatty acid-binding protein (FABP), a recently introduced early marker for acute myocardial infarction with a normal plasma concentration below 1 nmol/l, interleukin 6 (IL-6), a cytokine with normal plasma concentrations below 1 pmol/l, and again, annexin V. A possible future application of the method in the development of a one-step ELISA is discussed.
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- 1999
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24. Spotlight on fatty acids in cell signaling: The 13th FACS meeting.
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Glatz, Jan F.C. and Lagarde, Michel
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- 2020
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25. Fatty Acid Transfer Across the Myocardial Capillary Wall: No Evidence of a Substantial Role for Cytoplasmic Fatty Acid-binding Protein
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Van Nieuwenhoven, Frans A., Verstijnen, Cees P.H.J., Van Eys, Guillaume J.J.M., Van Breda, Eric, De Jong, Yvonne F., Van Der Vusse, Ger J., and Glatz, Jan F.C.
- Abstract
It has recently been hypothesized that fatty acid (FA) transfer across the myocardial capillary wall is mediated by cytoplasmic fatty acid-binding protein (FABP). Therefore, we studied the type and content of FABP in endothelial cells from rat heart, using molecular biological, immunochemical, and FA-binding assays. Studies were performed on short term cultured endothelial cells, two established endothelial cell lines and ultrathin cryosections from adult rat heart. Northern blotting analysis of endothelial cell RNA failed to detect either heart-type (H-) FABP or liver-type (L-) FABP mRNA, but the reversed transcription-polymerase chain reaction revealed both H- and L- FABP mRNAs, indicating the presence of minor amounts of these mRNAs. Highly sensitive immunochemical assays (sandwich ELISAs) using specific antibodies raised against rat H- or L-FABP showed the contents of these FABP-types in endothelial cells to be 1-5 ng/mg cytosolic protein, which is more than three orders of magnitude lower than the contents of H-FABP in heart or L-FABP in liver. Immuno-electron microscopy also showed that the concentration of H-FABP in endothelial cells is at least two orders of magnitude lower than that in cardiomyocytes. Finally, cytosolic protein samples from endothelial cells revealed no significant FA-binding activity in the 15-kDa region. We conclude that rat heart endothelial cells contain only minor quantities of cytoplasmic FABP and that, therefore, FA transport over the endothelium is mediated by FABP only to a minor extent. It is postulated that aqueous diffusion of FA through the endothelial cytoplasm most likely accounts for the experimentally observed rates of cardiac FA utilization.
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- 1994
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26. On the Mechanism of Long Chain Fatty Acid Transport in Cardiomyocytes as Facilitated by Cytoplasmic Fatty Acid-binding Protein
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Vork, Michaël M., Glatz, Jan F.C., and Vusse, Ger J. Van Der
- Abstract
Fatty acid-binding protein (FABP) is abundantly present in the cytoplasm of the cardiomyocyte, i.e. the cell which causes the contractile activity of the heart. Although FABP is thought to act as an intracellular long chain fatty acid (FA) carrier, definite experimental proof on this putative function has yet to be obtained. In the present study, experimental results from several authors were combined in an attempt to elucidate the precise physiological function of heart-type FABP in cardiac FA transport. It was calculated that, under normal conditions, the major part of FA in the cardiomyocyte is dissolved in lipid bilayers and that the presence of FABP in the heart enhances the aqueous solubility of FA more than 700-fold despite the fact that only a minor part (<2%) of the total FABP content is then complexed with FA. Moreover, it is shown that, as a result of the enhanced cytoplasmic solubility, the FA flux from sarcolemma (the cellular membrane of the cardiomyocyte) to mitochondria is increased at least 17-fold in the presence of physiological amounts of FABP compared with the hypothetical situation in which FABP is absent. These calculations indicate the involvement of FABP in the transport of FA from the sarcolemma to those mitochondria lying in the innermost region of the cardiomyocyte. The extent to which FABP facilitates FA trafficking through the cytoplasm of the cardiomyocyte under physiological circumstances remains, however, to be established. Copyright 1993, 1999 Academic Press
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- 1993
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27. PS9 - 12. Involvement of zinc in the fatty acid transport function of CD36: a novel link to type 2 diabetes
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Angin, Yeliz, Dikkenberg, Antoinette, Timmers, H.Th. Marc, Horst, Dick J., Coumans, Will A., Neumann, Dietbert, Glatz, Jan F.C., Rodenburg, Kees W., and Luiken, Joost J.F.P.
- 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.
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- 2013
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28. Spotlight on cellular lipid binding proteins.
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Glatz, Jan F.C.
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- 2015
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29. PS9 - 42. Contraction-induced increase in muscle glucose uptake requires dual signaling input – Consequence for muscle glucose utilization in diabetes
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Luiken, Joost J.F.P., Neumann, Dietbert, and Glatz, Jan F.C.
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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.
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- 2012
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30. Lipids in metabolic health and disease.
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Glatz, Jan F.C., de Groot, Renate H.M., Hesselink, Matthijs K.C., and Schrauwen, Patrick
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- 2011
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31. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses.
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Crispi, Fatima, Hernandez-Andrade, Edgar, Pelsers, Maurice M.A.L., Plasencia, Walter, Benavides-Serralde, Jesus Andres, Eixarch, Elisenda, Le Noble, Ferdinand, Ahmed, Asif, Glatz, Jan F.C., Nicolaides, Kypros H., and Gratacos, Eduard
- Subjects
FETAL growth retardation ,FETAL heart ,FATTY acid-binding proteins ,ATRIAL natriuretic peptides ,DOPPLER ultrasonography ,FETAL development ,CARDIAC output ,CORD blood ,PHYSIOLOGY - Abstract
Objective: The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration. Study Design: One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid–binding protein, troponin-I, and high-sensitivity C-reactive protein. Results: Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid–binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage. Conclusion: IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage. [Copyright &y& Elsevier]
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- 2008
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32. PS6 - 2. ‘Tour d’AMPK’: Myocellular cycling of the energy sensor AMPK between free and glycogen-bound states
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Oligschläger, Yvonne, Miglianico, Marie, Chanda, Dipanjan, Scholz, Roland, Thali, Ramon F., Türk, Roland D., Glatz, Jan F.C., and Neumann, Dietbert
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Disposal of glucose into muscular glycogen is diminished in type 2 diabetes (T2D). In response to various cellular stress signals, AMP-activated protein kinase (AMPK; αβγ) affects key metabolic pathways to equilibrate energy intake and expenditure. In muscle, activated AMPK increases insulin-independent glucose import, while inhibiting glycogen synthesis due to phosphorylation of glycogen synthase located at glycogen.
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- 2013
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33. PS10 - 3. Contraction-induced glucose uptake requires dual signaling input: Consequence for muscular glucose utilization in diabetes
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Luiken, Joost J.F.P., Dirkx, Ellen, Neumann, Dietbert, and Glatz, Jan F.C.
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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.
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- 2013
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34. PS9 - 43. Overexpression of vesicle-associated membrane protein-3 (VAMP3) protects against lipid-induced inhibition of insulin-stimulated GLUT4 translocation in cardiomyocytes
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Schwenk, Robert W., Angin, Yeliz, Steinbusch, Laura K.M., Dirkx, Ellen, Hoebers, Nicole, Coumans, Will A., Broers, Jos L.V., Eys, Guillaume J.J.M., Glatz, Jan F.C., and Luiken, Joost J.F.P.
- 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.
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- 2012
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35. PS9 - 41. Translocation of substrate transporters glut4 and cd36 to the sarcolemma and subsequent activation to increase substrate uptake are separate events
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Angin, Yeliz, Schwenk, Robert W., Unal, Reyhan N., Kerfant, Benoit-Gilles, Neumann, Dietbert, Glatz, Jan F.C., and Luiken, Joost J.F.P.
- 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.
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- 2012
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36. Peri-operative myocardial tissue injury and the release of inflammatory mediators in coronary artery bypass graft patients
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Fransen, Erik J, Maessen, Jos G, Hermens, Wim.Th, Glatz, Jan F.C, and Buurman, Wim A
- Abstract
Objective: This study was conducted to evaluate to what extent the ischemia-reperfusion injury resulting from the cardiopulmonary bypass (CPB) and aortic cross-clamping procedures during coronary artery bypass grafting (CABG) contributes to the systemic inflammatory response generally found in these patients. Methods: Serum levels of enzymes (CK and CK-MB) and non-enzymatic proteins (FABP and myoglobin) as markers of myocardial tissue injury, bactericidal permeability increasing protein (BPI) as an indicator of neutrophil activation, interleukin-6 (IL-6) as inducer of the acute phase response and lipopolysaccharide binding protein (LBP) as parameter of the acute phase response were measured in 15 low-risk CABG patients with cardiopulmonary bypass (CPB), and 17 low-risk CABG patients without CPB. Results: Already 0.5 h after reperfusion significantly increased plasma levels of all markers of myocardial tissue injury were noted in patients having surgery with CPB, but not in non-CPB patients. No significant differences were found between both groups for BPI and IL-6 levels in the early reperfusion period. BPI and IL-6 levels were higher in the non-CPB group on the first post-operative day (P<0.05). However, no correlations were found for any marker of peri-operative tissue damage with either early neutrophil activation, or acute phase reactants. Conclusions: Perioperative myocardial injury resulting from CPB and aortic cross-clamping in low-risk CABG patients does not contribute to the release of inflammatory mediators in these patients.
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- 2000
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37. Cardiac fatty acid uptake and transport in health and disease
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van der Vusse, Ger J, van Bilsen, Marc, and Glatz, Jan F.C
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Fatty acids are important energy donors for the healthy heart. These substrates are supplied to the myocardium bound to albumin to overcome their low solubility in aqueous solutions such as blood plasma. Transport from the microvasular compartment to the mitochondria inside the cardiomyocytes is most likely a combination of passive and protein-mediated diffusion. Alterations in tissue content of fatty acid-transport proteins may contribute to myocardial diseases such as the diabetic heart, and cardiac hypertrophy and failure.
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- 2000
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38. Measurement of myocardial infarct size from plasma fatty acid-binding protein or myoglobin, using individually estimated clearance rates
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de Groot, Monique J.M., Wodzig, K.Will H., Simoons, Maarten L., Glatz, Jan F.C., and Hermens, Wim Th.
- Abstract
Objective: In patients with acute myocardial infarction (AMI), estimation of infarct size from the early markers, fatty acid-binding protein (FABP) and myoglobin (MYO), usually assumes average (fixed) rate constants (FCR) for protein clearance from plasma. However, individual variation in FCR is large. Renal dysfunction causes slower clearance of FABP and MYO from plasma and, hence, overestimation of infarct size in 20–25% of patients. We investigated whether or not more accurate values of infarct size could be obtained with individually estimated clearance rates. Methods: Concentrations of FABP and MYO and, for comparison, activities of the established cardiac markers, creatine kinase (CK) and -hydroxybutyrate dehydrogenase (HBDH), were assayed in serial plasma samples from 138 patients with AMI. Individual FCR values of FABP and MYO were estimated from plasma creatinine concentrations, sex and age. Results: Individual FCR values varied from 0.4 to 2.4 h–1. Use of these individual FCR values significantly improved the correlation between infarct size, as estimated from FABP or MYO on the one hand, and from CK and HBDH on the other. Approximately equal estimates of infarct size were obtained for all four marker proteins. Conclusions: Using individually estimated clearance rates, renal insufficiency no longer hampers calculation of infarct size from FABP and MYO, and reliable estimates of total myocardial damage can be obtained within 24 h after first symptoms.
- Published
- 1999
- Full Text
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