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Integrated Regulation of Cardiac Fatty Acid and Glucose Oxidation
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- Author / Creator
- Altamimi, Tariq Rushdi
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Energy substrate utilization in the heart is both altered by- and contributes to- the pathophysiology of heart disease. For example, there is an increased reliance on fatty acid oxidation for energy production in conditions such as diabetes, diabetic cardiomyopathy, and during reperfusion of ischemic hearts. Fatty acids are less efficient energy substrates than glucose, and an increased use of fatty acids can increase the burden on energetically compromised hearts, contributing to cardiac dysfunction. Therefore, understanding the relationship between metabolism of fatty acids and glucose, the two major substrates competing for energy production in the heart, is essential to providing the knowledge required for developing new metabolic treatments to treat heart disease. Such therapies depend on targeting and modifying regulatory steps in this integrated relationship. To this aim, I explored in this thesis potential points of regulation of glucose and fatty acid oxidation at different levels and through several approaches. These included control of mitochondrial uptake of fatty acyl coenzyme A (CoA), mitochondrial calcium control of cardiac energy metabolism, control of fatty acid supply through endothelial cells, as well as the effects of a liver-secreted energy-modifying peptide hormone, adropin, on the regulation of fatty acid and glucose oxidation.
I first focused on exploring one regulatory process for mitochondrial fatty acid uptake, and hence oxidation, by investigating a potential cytosolic localization of an important metabolic enzyme, carnitine acetyltransferase (CrAT), known to reside in the mitochondrial and peroxisomal matrices. We found evidence of partial localization of CrAT in the cytosol of cardiomyocytes. This cytosolic CrAT could indirectly affect malonyl-CoA turnover in the cytosol, thereby influencing malonyl-CoA control of mitochondrial uptake of long-chain fatty acyl-CoAs and their subsequent mitochondrial oxidation. These results add to our knowledge of the importance of CrAT in the regulation of cardiac energy metabolism through a previously undiscovered cytosolic activity.
We then assessed what changes in cardiac energy metabolism ensue in response to impairment of mitochondrial calcium uptake, which is presumed to control cellular glucose oxidation. This was studied in a transgenic mouse model with a cardiac-specific deficiency of the mitochondrial calcium uniporter (MCU) channel protein, the primary gate for calcium influx through the inner mitochondrial membrane. Contrary to our expectations, MCU deficient mouse hearts showed higher cardiac work and uninhibited glucose oxidation rates, and when subjected to an inotrope challenge they displayed a normal rise in glucose oxidation but a greater stimulation of fatty acid oxidation. The underlying mechanism involved a stimulatory hyperacetylation of malonyl-CoA carboxylase, the enzyme responsible for degradation of the fatty acid oxidation inhibitor, malonyl-CoA. Our novel findings disagree with the previously proposed importance of MCU activity in the regulation of mitochondrial glucose oxidation.
To explore endothelial transport and supply of fatty acids to cardiomyocytes in the control of myocardial energy metabolism, we tested the recent proposal that impaired endothelial autophagy impairs trans-endothelial trafficking of fatty acids to neighboring cardiomyocytes. The autophagy-related protein 7 (ATG7) is an essential component of cellular autophagosome formation. Based on this, we utilized endothelial-specific ATG7 knockout (EC-ATG7-/-) mice to investigate the effect of impaired endothelial autophagy on cardiac energy metabolism in hearts subjected to both aerobic and ischemia/reperfusion (I/R) conditions. EC-ATG7-/- mouse hearts exhibited greater insulin-induced reduction of fatty acid oxidation compared to wild-type hearts, which was more marked under I/R conditions. Consistent with impaired fatty acid availability to the myocardial cells, EC-ATG7-/- hearts contained significantly lower triacylglycerol content, the major fatty acid storage form, compared to wild-type littermates. These results support an important role of endothelial autophagy in cardiomyocyte fatty acid metabolism.
We then investigated the effects of a liver-secreted factor, adropin, on cardiac energy metabolism. Intraperitoneal adropin injections both enhanced insulin signaling and cardiac function. Interestingly, acute adropin administration to isolated perfused hearts promoted glucose oxidation and insulin signalling, suggesting a direct and acute action of adropin, possibly through an undiscovered receptor. We propose adropin as a metabolic modulator and a potentially important target for the treatment of cardiac disease associated with impaired insulin sensitivity.
Overall, the results presented in this thesis provide novel insights into the control of cardiac fatty acid and glucose metabolism at different levels. Such information can broaden our scientific knowledge and help devise new therapeutic interventions aiming at optimizing energy homeostasis in heart disease. -
- Graduation date
- Fall 2018
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.