Showing papers by "Jan F. C. Glatz published in 2020"

CD36 (SR-B2) as a Target to Treat Lipid Overload-Induced Cardiac Dysfunction

Abstract: The heart faces the challenge of adjusting the rate of fatty acid uptake to match myocardial demand for energy provision at any given moment, avoiding both too low uptake rates, which could elicit an energy deficit, and too high uptake rates, which pose the risk of excess lipid accumulation and lipotoxicity. The transmembrane glycoprotein cluster of differentiation 36 (CD36), a scavenger receptor (B2), serves many functions in lipid metabolism and signaling. In the heart, CD36 is the main sarcolemmal lipid transporter involved in the rate-limiting kinetic step in cardiac lipid utilization. The cellular fatty acid uptake rate is determined by the presence of CD36 at the cell surface, which is regulated by subcellular vesicular recycling from endosomes to the sarcolemma. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Thus, in conditions of chronic lipid overload, high levels of CD36 are moved to the sarcolemma, setting the heart on a route towards increased lipid uptake, excessive lipid accumulation, insulin resistance, and eventually contractile dysfunction. Insight into the subcellular trafficking machinery of CD36 will provide novel targets to treat the lipid-overloaded heart. A screen for CD36-dedicated trafficking proteins found that vacuolar-type H+-ATPase and specific vesicle-associated membrane proteins, among others, were uniquely involved in CD36 recycling. Preliminary data suggest that these proteins may offer clues on how to manipulate myocardial lipid uptake, and thus could be promising targets for metabolic intervention therapy to treat the failing heart.

Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

Abstract: The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, which may ultimately lead to contractile dysfunction. This substrate shift is facilitated by increased translocation of lipid transporter CD36 (SR-B2) from endosomes to the sarcolemma resulting in increased lipid uptake. We previously showed that endosomal retention of CD36 is dependent on the proper functioning of vacuolar H+-ATPase (v-ATPase). Excess lipids trigger CD36 translocation through inhibition of v-ATPase function. Conversely, in yeast, glucose availability is known to enhance v-ATPase function, allowing us to hypothesize that glucose availability, via v-ATPase, may internalize CD36 and restore contractile function in lipid-overloaded cardiomyocytes. Increased glucose availability was achieved through (a) high glucose (25 mM) addition to the culture medium or (b) adenoviral overexpression of protein kinase-D1 (a kinase mediating GLUT4 translocation). In HL-1 cardiomyocytes, adult rat and human cardiomyocytes cultured under high-lipid conditions, each treatment stimulated v-ATPase re-assembly, endosomal acidification, endosomal CD36 retention and prevented myocellular lipid accumulation. Additionally, these treatments preserved insulin-stimulated GLUT4 translocation and glucose uptake as well as contractile force. The present findings reveal v-ATPase functions as a key regulator of cardiomyocyte substrate preference and as a novel potential treatment approach for the diabetic heart.

Mutations in PDLIM5 are rare in dilated cardiomyopathy but are emerging as potential disease modifiers

Abstract: Background A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. Methods We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole-exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. Results PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN-variant. The PDLIM5 loss-of-function (LoF) variant affected all cardiac-specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN-variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb-deletion of exon 2 in PDLIM5 resulting in early-onset cardiac disease, showing the importance of PDLIM5 in cardiac function. Conclusions Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early-onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers.

Putative Role of Protein Palmitoylation in Cardiac Lipid-Induced Insulin Resistance

Abstract: In the heart, inhibition of the insulin cascade following lipid overload is strongly associated with contractile dysfunction. The translocation of fatty acid transporter CD36 (SR-B2) from intracellular stores to the cell surface is a hallmark event in the lipid-overloaded heart, feeding forward to intracellular lipid accumulation. Yet, the molecular mechanisms by which intracellularly arrived lipids induce insulin resistance is ill-understood. Bioactive lipid metabolites (diacyl-glycerols, ceramides) are contributing factors but fail to correlate with the degree of cardiac insulin resistance in diabetic humans. This leaves room for other lipid-induced mechanisms involved in lipid-induced insulin resistance, including protein palmitoylation. Protein palmitoylation encompasses the reversible covalent attachment of palmitate moieties to cysteine residues and is governed by protein acyl-transferases and thioesterases. The function of palmitoylation is to provide proteins with proper spatiotemporal localization, thereby securing the correct unwinding of signaling pathways. In this review, we provide examples of palmitoylations of individual signaling proteins to discuss the emerging role of protein palmitoylation as a modulator of the insulin signaling cascade. Second, we speculate how protein hyper-palmitoylations (including that of CD36), as they occur during lipid oversupply, may lead to insulin resistance. Finally, we conclude that the protein palmitoylation machinery may offer novel targets to fight lipid-induced cardiomyopathy.

Myocardial Fatty Acid-Glucose Fuel Balance as Target to Treat Cardiac Diseases

Abstract: The currently most prevalent cardiac diseases, diabetic cardiomyopathy and hypertrophic heart failure, each associate with a chronic change in energy substrate utilization towards a single type of substrate, i.e., fatty acids or glucose, respectively. Recent experimental studies suggest that proper cardiac contractile performance is dependent on a finely tuned balance between the utilization of these two substrates. Furthermore, re-balancing myocardial fuel supply (fatty acids versus glucose) appears an effective treatment option in cardiac disease.

Metabolic Modulation to Treat Cardiac Diseases: Role for Membrane Substrate Transporters

Abstract: There is growing recognition of the importance and multiple roles of substrate energy metabolism in both cardiac health and disease. Cardiac diseases are frequently accompanied by altered myocardial metabolism, while chronic changes in the type of myocardial substrate utilization are found to elicit cardiac contractile dysfunction. Examples are the increased glucose utilization, at the expense of fatty acids, in cardiac hypertrophy and ischemic heart failure, and the increased fatty acid utilization, at the expense of glucose, in obesity and diabetes-related cardiac dysfunction. Modulation of cardiac metabolism has emerged as a suitable therapeutic intervention in cardiac disease. Insights obtained during the past decade have revealed sarcolemmal substrate transport, facilitated by CD36 for fatty acids and by GLUT4 for glucose, to represent the main rate-governing kinetic step of substrate utilization, over-ruling intracellular sites of flux regulation. This suggests that manipulating the presence of substrate transporters in the sarcolemma may be an effective approach for metabolic modulation therapy. The present mini-review provides a short summary of the functioning of substrate transporters CD36 and GLUT4 in the heart, and discusses their application as targets for metabolic intervention.