Lipid Trafficking is Affected by Sex and Mediates Pathophysiological Cardiac Hypertrophy

The heart relies on high fatty acid uptake to meet its large demand for energy-rich producing substrate. Acyl Coenzyme A synthetase 1 (ACSL1) indirectly facilitates cellular fatty acid uptake and is the first step in activating fatty acids for intracellular use. Female sex has also been correlated with greater myocardial reliance on fatty acids. This study examined the roles of ACSL1 and female sex on fatty acid metabolism in hearts under physiologic conditions and in the lipid-starved state of chronic heart failure. Mice with cardiac-restricted ACSL1 overexpression (αMHC-ACSL1) were used to study ACSL1 function in intact hearts. ACSL1-mediated vectorial acylation, the rapid esterification of a CoA ester to a free fatty acid forming an acyl CoA, accelerated rates of long-chain fatty acid (LCFA) uptake in beating hearts. ACSL1 had specific effects on intracellular lipid trafficking. Synthesis of ceramide sphingolipids increased in ACSL1 hearts with sex-dependence and without detriment to cardiac performance. Fatty acids were not stored in the large triacylglyceride pool or shuttled to mitochondrial beta-oxidation. Expression of sarcolemmal fatty acid transporters was found to have a novel cooperative role with ACSL1. In a mouse model of chronic heart failure, pathologic pressure overload, hypertrophic remodeling and systolic functional decline was mitigated by ACSL1 overexpression. Increased ACSL1 metabolic trapping restored depleted long-chain acyl CoA in hypertrophied hearts. ACSL1 beneficially affected hypertrophied hearts by reducing known cardiotoxic and increasing potentially cardioprotective ceramide species. Mitochondrial function, specifically anaplerotic flux, and the bionenergetic reserve that is typically compromised in failing hearts improved with ACSL1 overexpressing. This study also found that female sex alone accelerated LCFA uptake rates in beating hearts, and were partially mediated by female sex hormone dependent expression of ACSL1. Removal of female sex hormones slowed uptake rates to the male levels. Preliminary data indicated ACSL1 and female sex may be synergistic in preserving systolic function and dynamic usage of intramyocardial triacylglyceride in hearts subject to pressure overload stress that would lead to chronic failure. Overall, ACSL1 and female sex were found to have critical roles in mediating normal lipid metabolism and augmenting their function may prove to be beneficial in protecting the myocardium from chronic heart failure.