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New Insight into the Role of Myocardial Fatty Acid Uptake and Utilization in Health and Disease Open Access

Descriptions

Other title
Subject/Keyword
Metabolism
Cardiac
Fatty Acid
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Nagendran, Jeevan
Supervisor and department
Dyck, Jason RB (Pediatrics)/ McAlister, Finlay A (Medicine)
Examining committee member and department
Dyck, Jason RB (Pediatrics)
McAlister, Finlay A (Medicine)
Ross, David B (Surgery)
Madsen, Karen (Medicine - exam committee chair)
Legare, Jean-Francois (Surgery, Dalhousie University)
Cheung, Po-Yin (Pediatrics)
Department
Department of Medicine
Specialization
Experimental Medicine
Date accepted
2013-06-26T10:35:00Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
All mammalian cells rely on adenosine triphosphate (ATP) to maintain function and for survival. The heart has the highest basal ATP demand of any organ due to the necessity for continuous contraction. As such, the ability of the cardiomyocyte to monitor cellular energy status and adapt the supply of substrates to match the energy demand is crucial. However, despite having basal energy demands exceeding those of any other organ in the body, cardiomyocytes do not possess large reserves of substrates required to form high-energy. As such, the heart must rely on exogenous substrate supply to be transported into the cardiomyocytes in order to be catabolized and to produce ATP. Because of this, continuous transport of substrates such as fatty acids (FAs), glucose, and lactate into the cardiomyocytes is a key component of cardiac energy metabolism. During normal physiological conditions, this production of ATP is met almost entirely (>95%) through oxidative phosphorylation. Specifically, FA oxidation is responsible for the generation of 50–70% of ATP in a normal adult heart while only 20–30% of the energy provided is derived from glucose and less than 5% from other sources. Herein, we review the involvement of myocardial FA uptake and subsequent utilization as it relates to cardiac function in physiologic and pathophysiologic processes. Specifically, we examine the cardiomyocyte-specific role of CD36, a FA transport protein, during ischemia-reperfusion injury. Utilizing an inducible cardiomyocyte-specific CD36 ablation mouse model, we provide genetic evidence that reduced FA oxidation as a result of diminished CD36-mediated FA uptake improves post-ischemic cardiac efficiency and functional recovery. As such, targeting cardiomyocyte FA uptake and FA oxidation via inhibition of CD36 in the adult myocardium may provide therapeutic benefit during ischemia-reperfusion. Furthermore, we examine the cardiomyocyte-specific role of adipose triglyceride lipase (ATGL) overexpression during doxorubicin induced cardiac dysfunction. Our data suggest that chronic reduction in myocardial triacylglycerol (TAG) content by cardiomyocyte-specific ATGL over-expression is able to prevent doxorubicin-induced cardiac dysfunction. We also examine the role of AMPK inhibitory phosphorylation of acetyl CoA carboxylase during high workload and ischemia-reperfusion injury. Our findings challenge the previously suggested role of AMPK-mediated ACC phosphorylation and inactivation as having a major role in the regulation of substrate metabolism and function in healthy and stressed myocardium. As well, since diabetes is one of the pathophysiologic processes known to cause alterations in FA metabolism in the myocardium, we further examined the effects of glucose-lowering medication on early outcomes of patients that had and acute coronary syndrome event. The work presented also emphasizes areas that require further investigation for the purpose of eventually translating this information into improved patient care.
Language
English
DOI
doi:10.7939/R36W96H9N
Rights
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.
Citation for previous publication
Nagendran J, Waller TJ, Dyck JRB. AMPK Signaling and the Control of Substrate use in the Heart. Molecular and Cellular Endocrinology, 2013; Feb 25;366(2):180-93.Nagendran J, Oudit GY, Bakal JA, Light PE, Dyck JRB, McAlister FA. Are users of sulfonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? Diabetes, Obesity, and Metabolism, 2013 May 13. [Epub ahead of print]Nagendran J, Kienesberger PC, Pulinilkunnil T, Zordoky B, Young ME, Zechner R, Dyck JRB. Cardiomyocyte-Specific ATGL Over-Expression Prevents Doxorubicin-Induced Cardiac Dysfunction in Female Mice. Heart. 2013 May 23. [Epub ahead of print]

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