Abstract 19008: ATP-Dependent Citrate Lyase Drives Cardiac Left Ventricular Dysfunction by Metabolic Remodeling

Abstract

Introduction: Cardiovascular diseases and cancer are the leading causes of death worldwide. Recurrent mutations of metabolic enzymes in cancer cells benefit tumor growth, creating a systemic metabolic phenotype and increasing the risk for adverse cardiac events. Computational analysis revealed an oncometabolic phenotype in the heart, characterized by a switch from oxidative towards reductive carboxylation of α-ketoglutarate and citrate. Our studies identified the ATP citrate lyase (ACL) as a critical regulatory enzyme driving metabolic adaptation during cancer by increasing acetyl-CoA synthesis and histone 3 acetylation in the heart. Hypothesis: We hypothesized that ACL is crucial for cardiac adaptation during oncometabolic stress. Methods: To answer these questions, we developed a cardiac-specific mouse model lacking ATP citrate lyase using clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)9 genomic editing. Cas9-Myh6-dtTomato mice (n=14-17 male and female mice/group) were subcutaneously injected 6 days after birth with single gRNA targeting the Acly locus. Cardiac function was monitored using echocardiographic examinations weekly between 12 and 20 weeks. We used in vivo [ 18 F]-FDG-positron emission tomography (PET) and stable isotope tracer labeling to identify and quantify metabolic alterations in vivo in response to the loss of ACL. Results: Knockdown of ACL causes left ventricular systolic dysfunction as evidenced by significantly reduced ejection fraction and an increased left ventricular diameter. In vivo [ 18 F]-FDG-PET revealed that loss of ACL increased plasma glucose uptake which is consistent with maladaptive metabolic remodeling and impaired oxidative metabolism during heart failure. RNA-sequencing followed by pathway enrichment analysis revealed differential expression of genes involved in mitochondrial function and lipid metabolic processes. Mass spectrometry-based metabolic flux analysis showed an increased malate m+2 to citrate m+2 ratio, consistent with reduced citrate efflux from the mitochondria towards the cytosol. Conclusions: ACL activity regulates reductive citrate flux and drives metabolic adaptation associated with cardiac dysfunction