Le rôle protecteur de la périlipine 2 dans la cardiomyopathie diabétique
The accumulation of lipids in the ER alter its functions and homeostasis which triggers a signalling pathway called ER stress (ERS). This pathway is initially programmed to recover ER homeostasis, but prolonged, it triggers an apoptosis cascade. Absorbed lipids are routed to the ER where they are converted to diacylglycerides (DAGs) and triacylglycerides (TAGs) which are packaged into lipid droplets. Lipid droplets contain a core of TAG and cholesterol esters which are converted by a phospholipid monolayer with associated proteins. In our laboratory, we are interested in investigating the mechanisms of lipotoxicity in the setting of diabetic cardiomyopathy.  We demonstrated that palmitate, the most abundant saturated fatty acid in the human diet, triggers ERS in H9c2, a cardiomyoblast cell line. This stress is accompanied with a lack of lipid droplets, accumulation of DAGs in the ER, and followed by a high mortality of cells via the activation of an apoptotic pathway. Moreover, palmitate causes the degradation of Plin2, a partial reduction of Plin3 expression, while Plin5 is intact. In contrast, oleate, the most abundant mono-unsaturated fatty acid in human diet, induces the formation of abundant lipid droplets but does not cause ERS nor DAG accumulation in the ER compartments. Plin2 degradation is also a result of ERS inducers that are independent of lipids associated mechanisms like tunicamycin and thapsigargin. The lack of Plin2 in these two conditions has no effect on the lipid droplets formation nor on the TAG synthesis. On the other hand, inhibition of proteasome slightly protected Plin2 and reduced the palmitate-associated cell death. Moreover, the co-administration of oleate with palmitate reduced the cell death and induced Plin2 expression, both in an oleate dose-dependant way. Finally, overexpressing Plin2 reduces palmitate-associated ERS and cell death. In brief, Plin2 plays a protective role against ERS. This mechanism seems partially independent of lipids which is a novel function of Plin2.
Diabetic Cardiomyopathy Lipotoxicity ER stress Lipid Droplet Perilipin 2