Understanding the distinct subcellular trafficking of CD36 and GLUT4 during the development of myocardial insulin resistance

Abstract

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The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

“…Lipid overexposure that changes the pH of endosomes not only contributes to the traffic of CD36 to sarcolemma, but also to GLUT-4 from endosomes to non-endosomal storage, in which it becomes trapped. The translocation of both is a vesicle-mediated process requiring specific vesicle-associated membrane proteins (VAMPs) [ 141 ]. The manipulation of selective VAMP expression in cardiomyocytes is a potential way to prevent the development of insulin resistance [ 142 ].…”

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

“…Still, there are subtle differences in their trafficking. Although endosomes represent the main intracellular storage for CD36, GLUT4 is additionally kept in multiple compartments named GLUT4 storage vesicles (GSVs), which either overlap with the endosomes or are found outside of this organelle [4,31]. In adipocytes, GSVs contain about half of the intracellularly stored GLUT4 (the other half in the endosome) [32].…”

“…Besides CD36, GLUT4 is also ejected from the endosomes under conditions of lipid overload. However, GLUT4 travels to other intracellular storage compartments, most likely GLUT4 storage vesicles (GSVs), without reaching the plasma membrane [31]. Increased trafficking of CD36 to the cell surface and the consequently chronically increased fatty acid uptake rates culminate into the intracellular accumulation of triacylglycerol, diacylglycerol (DAG) and ceramide (CER) of which the latter two lipid species inhibit the insulin cascade at the level of IRS-1 and Akt2 phosphorylation, respectively.…”

“…As described in Section 2.1, GLUT4 subcellular vesicles (GSV) in cardiomyocytes contain VAMP-2, which interacts with its cognate target membrane-associated SNAREs (t-SNAREs) SNAP23 and syntaxtin4 to promote the tethering of GLUT4 with the sarcolemma [31]. VAMP-2, SNAP23 and syntaxtin4 each are palmitoylated in adipocytes [26,108].…”

Targeting metabolic pathways to treat cardiovascular diseases

“…Together, CD36 and GLUT4 determine the substrate preference of the heart, i.e., the fatty acid-glucose fuel balance. Recent studies by Joost Luiken et al [6] have disclosed trafficking proteins that are distinctly involved in CD36 and GLUT4 vesicular trafficking. These trafficking proteins, in particular vacuolar-type H + -ATPase and specific vesicle-associated membrane proteins (VAMPs), offer promising targets to rectify aberrant substrate uptake rates and restore a proper fatty acid-glucose fuel balance.…”