Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in theob/obModel of Obesity

Cardiac lipotoxicity is associated with structural remodeling and functional changes that are features of obesity-related cardiomyopathy. Both high fat diet and the ob/ob mutation lead to increased fatty acid (FA) uptake, elevated triacylglycerol (TAG) content, hypertrophy, and systolic and diastolic dysfunction in murine hearts. Cardiomyocyte-specific long-chain acyl-CoA synthetase 1 (ACSL1) deficiency ( Acsl1 H -/- ) results in a 90% reduction in FA activation, suggesting that Acsl1 ablation might alleviate obesity-associated myocardial dysfunction. Double knockout ob-Acsl1 H -/- and ob-Acsl1 flox/flox control mice were treated with tamoxifen at 20 weeks of age; heart function, TAG content, and relevant gene expression were assessed immediately before and 2 and 5 weeks after treatment. Heart weights initially increased in lean and obese Acsl1 H -/- mice, but normalized in ob-Acsl1 H -/- mice by 5 weeks. Ventricular TAG content was decreased by 51% and 61% in ob-Acsl1 H -/- mice 2 and 5 weeks after Acsl1 knockout induction, respectively. Moreover, ACSL1 knockout resulted in increased survival of ob/ob mice, suggesting that lack of ACSL1 protected obese hearts subjected to stress. Our results indicate that partial knockdown of cardiac ACSL1 is sufficient to reverse cardiac TAG accumulation and to ameliorate heart dysfunction even in the context of established obesity-related cardiomyopathy.