AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression

Figure 6

Schematic representation of the potential mechanisms by which AICAR regulates cardiac metabolism and protects HL-1 cardiomyocytes from the HP/HI-induced lipotoxicity and insulin resistance. HP/HI stimulation induces insulin resistance by promoting the intramyocellular lipid build-up, which in turn inhibits the insulin signalling pathway and the AKT-mediated GLUT4 membrane translocation and glucose uptake. AICAR treatment takes part in the regulation of the cardiac metabolic adaptation at several levels. First, AICAR short-term stimulation promotes the inhibition of ACC, thereby reducing the levels of the allosteric inhibitor of CPT-1 malonyl-CoA and regulating the fatty acid mitochondrial β-oxidation. In addition, AICAR-induced AMPK activation promotes GLUT4 membrane translocation through non-insulin dependent mechanisms. Finally, AICAR stimulation induces the three PPARs mRNA levels and controls the expression of some key PPAR-target genes, such as Acadvl and Glut4, involved in both glucose and fatty acid cardiac metabolism. Therefore, through these different mechanisms, AICAR is able to regulate both the acute metabolic response and the long-term metabolic adaptation in cardiac cells.