Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction
Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G. McDonald, Chongshan Dai, Chao Li, Zhao V. Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R. Malloy, Stanislaw Deja, Shawn C. Burgess, Matthew A. Mitsche, Jay D. Horton
Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G. McDonald, Chongshan Dai, Chao Li, Zhao V. Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R. Malloy, Stanislaw Deja, Shawn C. Burgess, Matthew A. Mitsche, Jay D. Horton
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Research Article Cardiology Metabolism

Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction

Abstract

Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

Authors

Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G. McDonald, Chongshan Dai, Chao Li, Zhao V. Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R. Malloy, Stanislaw Deja, Shawn C. Burgess, Matthew A. Mitsche, Jay D. Horton

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Figure 1

Genetic deletion of ACC1 and ACC2 in mouse cardiomyocytes.

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Genetic deletion of ACC1 and ACC2 in mouse cardiomyocytes. (A and B) Tot...
(A and B) Total RNA was isolated from hearts of 10-week-old WT, ACC1 HKO, ACC2 HKO, and ACC dHKO male mice, and RT-qPCR was performed to measure Acc1 and Acc2 mRNA expression (n = 6 WT, 5 ACC1 HKO, 2 ACC2 HKO, and 5 ACC dHKO for A; n = 6 WT, 5 ACC1 HKO, 2 ACC2 HKO, and 5 ACC dHKO for B). ***P < 0.001, ****P < 0.0001 by 1-way ANOVA. (C) Hearts from 20-week-old WT and ACC dHKO female mice were harvested and freeze-clamped to measure malonyl-CoA and acetyl-CoA levels, as described in Methods (n = 6 WT and 7 ACC dHKO). ****P < 0.0001 by unpaired 2-tailed Student’s t test. (D–F) ECHO assessment of cardiac function in male ACC1 HKO, ACC2 HKO, and ACC dHKO mice at 2, 4, 6, and 9 months of age (n = 10 WT, 5 ACC1 HKO, 7 ACC2 HKO, and 5 ACC dHKO at 2, 4, and 6 months; n = 10 WT, 5 ACC1 HKO, 7 ACC2 HKO, and 4 ACC dHKO at 9 months). Data are presented as the mean ± SEM.