Unrestrained fatty acid oxidation in ACC double-knockout mice triggered heart failure via cardiolipin depletion and mitochondrial dysfunction, which was prevented by pharmacologic FAO inhibition.
Does pharmacologic inhibition of FAO prevent cardiac dysfunction in a mouse model of unrestrained FAO?
Unrestrained fatty acid oxidation causes heart failure in mice through cardiolipin depletion and mitochondrial dysfunction, suggesting that therapies stimulating cardiac FAO may be harmful.
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.
Kim et al. (Fri,) conducted a other in Heart failure. Pharmacologic inhibition of FAO with etomoxir or oxfenicine was evaluated on Cardiolipin levels, mitochondrial electron transport chain activity, and cardiac dysfunction. Unrestrained fatty acid oxidation in ACC double-knockout mice triggered heart failure via cardiolipin depletion and mitochondrial dysfunction, which was prevented by pharmacologic FAO inhibition.