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 2

Decreased heart function in ACC dHKO mice.

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Decreased heart function in ACC dHKO mice. (A) Transverse/2-chamber view...
(A) Transverse/2-chamber views of hearts from 11-month-old WT and ACC dHKO male mice. (B) Representative M-mode ECHO images from 10-month-old male WT and ACC dHKO mice. LVPW, left ventricular posterior wall. (C) ECHO assessment of cardiac function in 10-month-old WT and ACC dHKO male mice (n = 15 WT and 9 ACC dHKO). ****P < 0.0001 by unpaired 2-tailed Student’s t test. Data are presented as the mean ± SEM. (D) Total RNA was isolated from hearts of 10-week-old WT and ACC dHKO male mice, and RT-qPCR was performed to measure expression of hypertrophy-associated genes (Myh7, Nppa, and Nppb) (n = 5 WT and 5 ACC dHKO). *P < 0.05, ***P < 0.001 by unpaired 2-tailed Student’s t test. (E) Representative TC-stained sections from hearts of 11-month-old WT and ACC dHKO male mice are shown at ×10 magnification. Collagen area was quantified from TC-positive regions using multiple microscopy images from each group (11 images from 2 WT mice and 15 images from 3 ACC dHKO mice) with the split-red-channel method, as described in Methods. ****P < 0.0001 by unpaired 2-tailed Student’s t test.