Showing papers by "Jan F. C. Glatz published in 2011"

High fat diet induced diabetic cardiomyopathy

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.

Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes.

Abstract: Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy.

Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases.

Abstract: Background: There is a need for biomarkers in accessible matrices, such as blood, for the diagnosis of neurodegenerative diseases. The aim of this study was to measure the serum levels of brain-type fatty acid-binding protein (FABP) and heart-type FABP in patients with dementia-involving diseases. Methods: Brain- and heart-type FABP were measured in serum samples from patients with either Alzheimer's disease (AD) (n=31), Parkinson's disease (PD, n=43), or other cognitive disorders (OCD, n=42) and in 52 healthy controls. The localization of brain- and heart-type FABP was determined in brain sections by immunohistochemistry. Results: Brain-type FABP levels were elevated in serum of 29%, 35%, and 24% of the patients with AD, PD, and OCD, respectively, and in 2% of the healthy donors. Heart-type FABP serum levels were not different amongst the patient groups. Brain-type and heart-type FABP expression was observed in reactive astrocytes in brain sections of patients with AD. Conclusions: In contrast to heart-type FABP, serum levels of brain-type FABP are elevated in a significant proportion of patients with various neurodegenerative diseases and can therefore have importance for defining subgroups of these patients. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice

Abstract: Cardiac patients often are obese and have hypertension, but in most studies these conditions are investigated separately. Here, we aimed at 1) elucidating the interaction of metabolic and mechanoph...

Cardiac lipid content is unresponsive to a physical activity training intervention in type 2 diabetic patients, despite improved ejection fraction

Abstract: Increased cardiac lipid content has been associated with diabetic cardiomyopathy. We recently showed that cardiac lipid content is reduced after 12 weeks of physical activity training in healthy overweight subjects. The beneficial effect of exercise training on cardiovascular risk is well established and the decrease in cardiac lipid content with exercise training in healthy overweight subjects was accompanied by improved ejection fraction. It is yet unclear whether diabetic patients respond similarly to physical activity training and whether a lowered lipid content in the heart is necessary for improvements in cardiac function. Here, we investigated whether exercise training is able to lower cardiac lipid content and improve cardiac function in type 2 diabetic patients. Eleven overweight-to-obese male patients with type 2 diabetes mellitus (age: 58.4 ± 0.9 years, BMI: 29.9 ± 0.01 kg/m2) followed a 12-week training program (combination endurance/strength training, three sessions/week). Before and after training, maximal whole body oxygen uptake (VO2max) and insulin sensitivity (by hyperinsulinemic, euglycemic clamp) was determined. Systolic function was determined under resting conditions by CINE-MRI and cardiac lipid content in the septum of the heart by Proton Magnetic Resonance Spectroscopy. VO2max increased (from 27.1 ± 1.5 to 30.1 ± 1.6 ml/min/kg, p = 0.001) and insulin sensitivity improved upon training (insulin stimulated glucose disposal (delta Rd of glucose) improved from 5.8 ± 1.9 to 10.3 ± 2.0 μmol/kg/min, p = 0.02. Left-ventricular ejection fraction improved after training (from 50.5 ± 2.0 to 55.6 ± 1.5%, p = 0.01) as well as cardiac index and cardiac output. Unexpectedly, cardiac lipid content in the septum remained unchanged (from 0.80 ± 0.22% to 0.95 ± 0.21%, p = 0.15). Twelve weeks of progressive endurance/strength training was effective in improving VO2max, insulin sensitivity and cardiac function in patients with type 2 diabetes mellitus. However, cardiac lipid content remained unchanged. These data suggest that a decrease in cardiac lipid content in type 2 diabetic patients is not a prerequisite for improvements in cardiac function. ISRCTN: ISRCTN43780395

Exercise-induced modulation of cardiac lipid content in healthy lean young men

Abstract: Cardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for the cardiac lipid accumulation. Therefore, the aim of the present study was to investigate if elevating plasma FA concentrations by exercise results in an increased cardiac lipid content, and if this influences cardiac function and energy status. Eleven male subjects (age 25.4 ± 1.1 years, BMI 23.6 ± 0.8 kg/m2) performed a 2-h cycling protocol, once while staying fasted and once while ingesting glucose, to create a state of high versus low plasma FA concentrations, respectively. Cardiac lipid content was measured by proton magnetic resonance spectroscopy (1H-MRS) at baseline, directly after exercise and again 4 h post-exercise, together with systolic function (by multi-slice cine-MRI) and cardiac energy status (by 31P-MRS). Plasma FA concentrations were increased threefold during exercise and ninefold during recovery in the fasted state compared with the glucose-fed state (p < 0.01). Cardiac lipid content was elevated at the end of the fasted test day (from 0.26 ± 0.04 to 0.44 ± 0.04%, p = 0.003), while it did not change with glucose supplementation (from 0.32 ± 0.03 to 0.26 ± 0.05%, p = 0.272). Furthermore, PCr/ATP was decreased by 32% in the high plasma FA state compared with the low FA state (n = 6, p = 0.014). However, in the high FA state, the ejection fraction 4 h post-exercise was higher compared with the low FA state (63 ± 2 vs. 59 ± 2%, p = 0.018). Elevated plasma FA concentrations, induced by exercise in the fasted state, lead to increased cardiac lipid content, but do not acutely hamper systolic function. Although the lower cardiac energy status is in line with a lipotoxic action of cardiac lipid content, a causal relationship cannot be proven.

In obese Zucker rats, lipids accumulate in the heart despite normal mitochondrial content, morphology and long-chain fatty acid oxidation

Abstract: We aimed to determine whether an increased rate of long-chain fatty acid (LCFA) transport and/or a reduction in mitochondrial oxidation contributes to lipid deposition in hearts, as lipid accumulation within cardiac muscle has been associated with heart failure. In hearts of lean and obese Zucker rats we examined: (a) triacylglycerol (TAG) and mitochondrial content and distribution using transmission electron microscopy (TEM), (b) LCFA oxidation in cardiac myocytes, and in isolated subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria, and (c) rates of LCFA transport into cardiac vesicles. Compared to lean rats, in obese Zucker rats, lipid droplet size was similar but there were more (P 0.05). In contrast, sarcolemmal plasma membrane fatty acid binding protein (FABPpm) and fatty acid translocase (FAT/CD36) protein and palmitate transport rates into cardiac vesicles were increased (P < 0.05; +50%) in obese animals. Collectively these data indicate that mitochondrial dysfunction in LCFA oxidation is not responsible for lipid accumulation in obese Zucker rat hearts. Rather, increased sarcolemmal LCFA transport proteins and rates of LCFA transport result in a greater number of lipid droplets within cardiac muscle.

Diagnosing acute coronary syndrome in primary care: comparison of the physicians' risk estimation and a clinical decision rule.

Abstract: Background. Diagnosing acute coronary syndrome (ACS) in a primary care setting poses a diagnostic dilemma for physicians. Objective. We directly compared the diagnostic accuracy of a clinical decision rule (CDR) based on history taking and physical examination in suspected ACS with the risk estimates of the attending GP. Methods. In a prospective multicenter study, patients suspected of ACS were included by the GP. GPs were asked to estimate the probability (0%–100%) of the presence of ACS. GPs collected patient data, but they were not aware of the CDR and did not score the patient accordingly. Results. Two hundred and ninety-eight patients were included (52% female, mean age 66 years, 22% ACS). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.75 [95% confidence interval (CI) 0.68–0.82] for the GP risk estimate and 0.66 (95% CI 0.58–0.73) for the CDR. There was an agreement between the risk estimation of the GP and a CDR in 51% and the prevalence of ACS in predefined low-, intermediate- and high-risk groups was similar for the GP and CDR estimates. In the low-risk group, according to the GP, four patients (8.2%) suffered an ACS. These four patients were all identified by the decision rule as high risk. Conclusions. The GP classified patients as ACS or no ACS more adequately than the CDR, judged by the AUC. However, the use of a CDR in patients that are considered at low risk for ACS by the GP could reduce the amount of missed myocardial infarctions.

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPAR α/γ activity in microvascular endothelial cells

Abstract: Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10⁻⁸ and 10⁻⁷ M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ℜ∓ 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.

Challenges in Fatty Acid and lipid physiology.

Abstract: Lipids comprise a wide variety of substances that share the common feature of being insoluble in water but soluble in organic solvents. Fatty acids are important building blocks of lipids and they give a diversity and chemical specificity to the complex lipids found in natural fats and oils, comparable to that given by the amino acids to proteins. Because of their special characteristics and significance, fatty acids are commonly treated as a separate group. Together, fatty acids and lipids are increasingly being recognized as serving important roles in physiology. Thus, fatty acids and lipids serve as membrane constituents and in energy supply and fuel storage, but specific lipids also function in regulating a wide variety of cellular processes, including gene expression. The most notable example is that long-chain fatty acids and some oxygenated derivatives can bind and thereby activate nuclear receptor proteins, in particular the so-called peroxisome proliferator activated receptors (PPARs), which in turn influence the expression of specific genes like those involved in lipid metabolism. In this way, fatty acids act as signaling molecules regulating the cellular routes and capacity for lipid utilization. Within this context, also the role of retinoic acid, a derivative of vitamin A, as a major regulator of gene expression should be mentioned. Another development is the finding that the level of lipid storage, for instance in adipose tissue, can be sensed by specific compounds. The corollary is that lipid droplets can no longer be viewed as inert intracellular deposits but rather appear dynamic structures able to communicate with other intracellular compartments. Taken together, a dynamic interplay among lipids, proteins, and membranes is of central importance for the proper physiological regulation of cellular functions. Below, I will highlight examples of new developments in this exciting field together with challenges for future research.

Cardiodetect rapid test for the diagnosis of early acute myocardial infarction

Abstract: Two hundreds patients suspected of acute myocardial infarction presenting to the hospital with a median symptom onset of 2.3 h (IQR 1.7–4.0 h) were enrolled in this study. The diagnostic performances of CardioDetect®, a one-step immunotest for heart-type fatty acid-binding protein (H-FABP), and its combination with cardiac troponin I (cTnI) at admission and 2 h after admission, were compared with different cardiac markers. The H-FABP immunotest had better sensitivities (76.6% and 94.4%) than the other cardiac markers and better specificities (88.2% and 81.7%) than myoglobin at admission and 2 h after admission. Both sensitivity and negative predictive value increased to over 90.0% at 2 h after admission. The areas under the receiver operator characteristic curve for the combination of H-FABP with cTnI were the greatest at admission [0.834 (95% CI: 0.774–0.894)].

Lipids in metabolic health and disease.

Abstract: This special issue of PLEFA contains a selection of original research papers and brief surveys presented at the ninth biennial Congress of the International Society for the Study of Fatty Acids and Lipids (ISSFAL), held in Maastricht, the Netherlands from May 29 to June 2, 2010. The theme of the congress was ‘‘Lipids in Metabolic Health and Disease’’. Plenary lectures were given by renowned scientists from around the world, while selected topics were covered in concurrent sessions organised in three tracks: Lipids & Health, Lipids & Nutrition, and Biochemistry of Lipids. The Alexander Leaf Distinguished Scientist Award for Lifetime Achievement was presented to Norman Salem, Jr., Ph.D., University of Rochester, NY, for his major contribution to our current knowledge on docosahexaenoic acid (DHA). The winner of the Early Career Award was John Paul SanGiovanni, Ph.D., National Institutes of Health, Bethesda MD, for his studies on the relationship of long-chain polyunsaturated fatty acid intake with pathogenic processes. A new record was set for total attendance, which amounted to 609 participants from 38 countries. In order to encourage individuals early in their careers to do research in the area of fatty acids and lipids, 40 New Investigator Awards were provided. Nine of them entered a competition which included voting on a ballot form by all delegates. The three winners of the Top New Investigator Award (one for each track) were Giuseppe Astarita,