Abstract Body (Do not enter title and authors here): Background: ATP-citrate lyase (ACLY) is a cytosolic enzyme that plays a prominent role in lipogenesis and lipid bilayer synthesis. It is prominently expressed in liver, adipocytes, and highly proliferative cancer cells. Bempaproic acid, an ACLY inhibitor that requires hepatic activation, is currently approved for hyperlipidemia, and direct inhibitors are being pursued for treating cancer and metabolic associated disorders. The latter increasingly overlaps with myocardial disease, yet the impact ACLY inhibition has on cardiomyocytes or the heart remains largely unknown.
Methods: Cardiomyocytes, ex-vivo beating hearts, and in vivo hearts were studied using a selective ACLY inhibitor (BMS303141, ACLYi) or gene-targeted suppression. Metabolic fate mapping, gene/protein expression, and physiological effects, cytotoxicity, and redox and NAD+/NADH regulation were determined. Mice with reduced cardiac ACLY by AAV9-acly-shRNA or cardiomyocyte-selective inducible knockdown (cmAcly-KD) were studied.
Results: U₁₃C-glucose tracing identified an ACLY-dependent circuit involving ACLY metabolism of cytosolic citrate that becomes converts to malate and then moves back into mitochondria to bypass NADH-generating components of the tricarboxylic acid cycle. Acute inhibition of ACLY (ACLYi) caused dose-dependent myocyte cytotoxicity, but had no effect on fibroblasts. ACLYi acutely depressed myocyte and intact heart function, while hearts with chronically reduced Acly by AAV9-shRNA exhibited ventricular dilation and reduced function. Hearts with cmAcly-KD had reduced exertional capacity, and an exacerbated maladaptive response to sustained pressure overload. ACLYi in vitro and in vivo depressed NAD+/NADH ratio, and its restoration by exogenous NAD reversed both in vitro cytotoxicity and in vivo cardiac dysfunction. ACLY gene and protein expression are reduced in human failing myocardium, with greater transcriptional depression in patients with obesity and heart failure with preserved ejection fraction.
Conclusions: ACLY supports basal cardiomyocyte and cardiac function through maintenance of the NAD+/NADH balance, and is particularly important in settings of hemodynamic stress