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Amp-activated protein kinase in the heart : role in fatty acid delivery, fatty acid utilization and cell death Kewalramani, Girish

Abstract

Following hypoinsulinemia, glucose utilization is compromised and the myocardium switches to utilize fatty acids (FA). Previous studies have reported that PPAR-α promotes FA oxidation during chronic hypoinsulinemia. Whether the same modification also occurs in the heart during acute hypoinsulinemia and if AMP-activated protein kinase (AMPK) participates in the increase of cardiac fatty acid oxidation during this condition remains unclear. Using streptozotocin model of Type I diabetes, we report that in acute (4 days) diabetes AMPK by phosphorylating acetyl CoA carboxylase promotes cardiac fatty acid oxidation. Unexpectedly, in chronic diabetes (6 weeks), with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and PPAR-α through its regulation of downstream targets controls myocardial FA oxidation. In addition to its role in FA utilization, AMPK has been implicated in controlling FA delivery through its regulation of the FA transporter, CD36. Given that LPL derived FA is the principal source of energy during insulin resistance, the question of interest was whether cardiac AMPK can regulate LPL translocation to the vascular lumen to increase the exogenous FA pool. Using dexamethasone (DEX) as an acute model of insulin resistance, my study demonstrates that, following a single dose of DEX, nongenomic phosphorylation of stress kinases such as AMPK together with insulin facilitate LPL translocation to the myocyte cell surface. Besides metabolism, AMPK has been implicated in modulating cell death. The production of tumor necrosis factor alpha (TNF-α) is reported to increase during obesity and diabetes and elevated plasma or endogenous cardiac TNF-α levels have shown to cause cardiomyocyte apoptosis. Using established AMPK activators like DEX or metformin (MET), my objective was to determine if AMPK activation prevents TNF-α-induced apoptosis in cardiomyocytes. My data demonstrates that although DEX and MET are used as anti-inflammatory agents or insulin sensitizers, their common property to phosphorylate AMPK promotes cardiomyocyte survival through its regulation of Bad and the mitochondrial apoptotic mechanism.

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