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Roles of AMPK in the regulation of cardiac metabolism and cell death An, Ding

Abstract

As a metabolic switch, AMP activated protein kinase (AMPK) is known to regulate energy metabolism. Activation of cardiac AMPK has been observed during ischemia, hypoxia, or exercise. It is unclear whether the same alteration occurs following hypoinsulinemia. Using streptozotocin (STZ) induced Type 1 diabetes, we report for the first time that in the acute (4 days) STZ diabetic heart, AMPK, but not PPAR-α, is activated. This activation of AMPK likely increases FA oxidation through phosphorylation and inhibition of acetyl-CoA carboxylase (ACC). In chronic diabetes, augmented plasma lipids and expression of CD36 provide the heart with excess FA. In this condition, PPAR-α, through its regulation of gene expression, likely contributes to high FA oxidation, while AMPK is normalized. In addition to FA oxidation, AMPK is also known to increase FA uptake through activation of CD36. Given that FA released from lipoprotein is suggested to be the main FA source supply to the heart, and lipoprotein lipase (LPL) is the primary enzyme controlling lipoprotein metabolism, of interest to us was the question of whether AMPK also influences FA delivery through LPL. Using fasting and modulators of AMPK, a strong correlation between this metabolic switch and cardiac LPL activity was established. To test whether β-adrenergic agonism could influence cardiac AMPK and heparin-releasable LPL, the β-adrenergic agonist isoproterenol was applied in different models. We found that only during conditions of increased workload and excessive energy expenditure, cardiac AMPK is activated and is highly associated with coronary heparin-releasable LPL activity. Finally, beside its role in the regulation of metabolism, recent studies suggest that AMPK can also modulate cell death. Given that AMPK, through elevation of FA oxidation, reduces lipid accumulation, it is unclear whether this process can protect cardiomyocytes against high fat induced cell apoptosis. Our study demonstrates that low doses of metformin reduce high fat induced cardiac cell death, likely through its effects in decreasing ceramide formation and caspase-3 activity. However, through its role in increasing proton accumulation and lactic acidosis, metformin can induce cardiomyocyte cell damage in a caspase-3 independent manner.

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