Clark, Hilary Stewart; (2002) The regulation of heart AMP-activated protein kinase by long-chain fatty acids and hormones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Malonyl-CoA plays a role in the regulation of cardiac β-oxidation due to its ability to inhibit carnitine palmitoyltransferase 1. Acetyl-CoA carboxylase (ACC) is the enzyme responsible for the synthesis of malonyl-CoA, the concentration of which increases in hearts exposed to glucose and insulin and is decreased by physiological concentrations of fatty acids and by adrenaline. ACC is phosphorylated and inhibited in response to the activation of the AMP- activated protein kinase (AMPK) cascade. Both α-1 and α-2 AMPK isoforms are phosphorylated and activated in hearts perfused with physiological concentrations of palmitate. This activation is not associated with alterations in the ratio of AMP to ATP. The activity of both AMPK isoforms is decreased after exposure to insulin, an effect overcome by 0.5mM palmitate. The activity of α-1 AMPK is stimulated in glucose perfused hearts by adrenaline, with rates similar to those measured in hearts perfused with 0.5mM palmitate. Adrenaline failed to increase α-1 AMPK activity above that due to fatty acids in palmitate perfused hearts. Adrenaline stimulation of palmitate perfused hearts resulted in a reversal of the effect of this fatty acid on α-2 AMPK activity. Adrenaline was without effect on the activity of this isoform in hearts perfused with glucose as the sole substrate. ACC was highly phosphorylated at the AMPK site in tissue from hearts exposed to 0.5mM palmitate compared to those perfused with glucose alone. However despite this, no alteration in ACC activity could be measured in response to palmitate and hormones in this study except for a small decrease due to adrenaline in palmitate perfused hearts.

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