The overall goal is to elucidate and mitigate mechanisms of maladaptive metabolic remodeling that may contribute to cardiac dysfunction and the progression to decompensated cardiac hypertrophy. The proposal originates from novel findings in our laboratory: 1) that stored triglyceride (TG) in the heart is quite dynamic, but TG turnover is slow in failing hearts as is TG content, the latter being confirmed in heart failure patients without diabetes. The loss of TG turnover reduces the contribution of long chain fatty acids (LCFA) from TG to fatty acid oxidation (FAO) and impairs TG lipolytic activation of PPAR?. We have reported that while palmitate sustains this reduced TG metabolism and PPAR? activation in hypertrophied hearts, oleate normalizes each of these very same parameters; 2) Our lab first reported increased protein content of the liver isoform of the rate limiting enzyme in FAO, carnitine palmitoyltransferase I (CPT1) in hypertrophied hearts. We also found acute expression of the liver CPT1 (CPT1a) in healthy hearts induced two surprising results; a paradoxical reduction in FAO and elevated myocardial atrial natriuretic peptide mRNA, both classically observed responses to [ pathogenic stress. 3) Preliminary data show isoform specific acylation and responses to TAC. 4) CPT1a expression is suppressed by Mir-370 and that Mir370 content is low in hypertrophied hearts. Thus, we hypothesize that: 1) Supplying an oleate rich diet provides benefits to rat hearts following transverse aortic constriction (TAC) by a) maintaining TG turnover and PPAR? target gene expression, b) influencing the formation of ceramide species, and c) thereby attenuating dysfunction and decompensation. 2) Increased CPT1a in hypertrophied hearts is a key step in the early metabolic remodeling that influences cardiac decompensation and is linked to hypertrophic signaling. 3) Increased CPT1a in hypertrophied hearts is linked to reduced FAO via changes in isoform-specific, CPT1 acetylation and malonylation, and these changes respond to CPT1a regulation via restored Mir-370.
Aim 1 a) determines effects of palmitate- (tripalmitin) ] versus oleate-rich (triolein) diets on decompensation after TAC in rat hearts, and b) determines if triolein and tripalmitin diets post-TAC affect TG turnover, PPAR? target gene expression, LCFA oxidation and lipotoxic acyl-intermediates.
Aim 2 determines the role of the isoform shift to CPT1a (liver) expression in the reduced LCFA oxidation and progression toward decompensation and early HF. Cardiac specific, CPT1a null mice, that [ are unable increase CPT1a in response to TAC, will be examined for functional and hypertrophic responses to TAC. The potential for altered FAO through exclusive changes in CPT1b isoform content and acylation, will be elucidated in the restricted absence of a CPT1a response.
Aim 3 elucidates potentially maladaptive ] upregulation of CPT1a, due to reduced Mir-370 during TAC, and the role of CPT1a expression in acetylation and malonylation of both CPT1 isoforms. Low Mir-370 following TAC in rat hearts will be countered by acutely overexpressing Mir-370 to suppress CPT1a and downstream effects.

Public Health Relevance

This study explores mechanisms for maladaptive remodeling of lipid storage and oxidation dynamics that contribute to cardiac dysfunction and the progression of toward failure in response to chronic pathologic stress on the heart. Based on our findings, protocols test dietary control of specific long chain fatty acid supply to the pressure overloaded heart that may mediate progression of cardiac decompensation through the dynamic nature of stored triglyceride in heart muscle to serve as a source of gene activation and oxidative energy production. Experiments will also elucidate the consequences of gene expression shifts between different forms of the key enzyme that controls fat oxidation, carnitine palmitoyltransferase I, on remodeling of energy production pathways during cardiac pressure overload. The impact of this work will be: 1) identifying mechanisms by whether dietary can induce or counter maladaptive remodeling of metabolism in failing hearts; 2) elucidating new metabolic mechanisms at the levels of enzyme expression and modification that regulate , fatty acids as fuels for energy metabolism in normal and diseased hearts.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Liew, Chong Wee; Xu, Shanshan; Wang, Xuerong et al. (2017) Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy. Circ Heart Fail 10: