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.
Highlights
Chronic lipid overload of the heart, as occurs, for instance, during obesity, is known to have major consequences for cardiac functioning and may elicit cardiac disease
As revealed in studies in adipocytes and skeletal muscle, many proteins of the insulin signaling cascade and trafficking machinery involved in the translocation of GLUT4 and CD36 to the plasma membrane appear to be modulated by palmitoylation
Palmitoylation of CD36 in adipocytes is mediated by DHHC4 and DHHC5 [127], which are, respectively, the second and the third most abundantly expressed PATs in rat cardiomyocytes [61]
Summary
Chronic lipid overload of the heart, as occurs, for instance, during obesity, is known to have major consequences for cardiac functioning and may elicit cardiac disease. Unlike other kinds of protein lipidation, such as myristoylation and prenylation that are irreversible modifications [6,7,8], palmitoylation occurs in a dynamic and reversible fashion. Since protein palmitoylation within cardiac insulin signaling is virtually unexplored, we collect information from studies in (mainly) skeletal muscle and fat to summarize current knowledge over the physiological role of S-acylation within the insulin cascade and the uptake of energy substrates (Section 4).
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