Abstract OEC103: ATP-dependent Citrate Lyase Drives Metabolic Remodeling In The Heart During Cancer

Abstract

Cardiovascular diseases and cancer are the leading causes of death worldwide. Recurrent mutations of metabolic enzymes in cancer cells provide benefits for tumor growth, while creating a systemic metabolic phenotype and increasing the risk for adverse cardiac events. We recently showed that tumors producing the oncometabolite D-2-hydroxyglutarate increase ATP citrate lyase activity and histone acetylation in the heart. How cancer cells drive metabolic remodeling in the heart, and whether ATP citrate lyase is critical for cardiac adaptation during cancer, remains poorly understood. We co-cultured wildtype adult mouse ventricular cardiomyocytes with colorectal cancer cells overexpressing ATP citrate lyase. Co-culture of cardiomyocytes with colorectal cancer cells was associated with reduced expression of ATP citrate lyase, pyruvate dehydrogenase, and mitochondrial complex I, suggesting that the cancer cell environment impaired mitochondrial function in vitro. In vitro modulation of ATP citrate lyase activity abrogated the metabolic alterations in cultured cardiomyocytes indicating that ATP citrate lyase drives remodeling during cancer. Accordingly, we created mice lacking ATP citrate lyase in the heart using CRISPR-Cas 9 genomic knockout. Loss of ATP citrate lyase leads to left ventricular systolic dysfunction and causes global gene and protein expression changes in the heart. Targeted mass spectrometry-based metabolomics and lipidomics showed decreased acetyl-CoA and succinyl-CoA levels in isolated cardiomyocytes, while the abundance of cholesterol esters increased. In vivo [ 18 F]-FDG-positron emission tomography revealed that animals lacking ATP citrate lyase increased plasma glucose uptake compared to animals with cardiac ATP citrate lyase expression. These findings are consistent with maladaptive metabolic remodeling and impaired oxidative metabolism during heart failure. Manipulating the activity of ATP citrate lyase using BMS303141 (0.5 μM) in ex vivo perfused wildtype rat hearts caused a rapid decline in cardiac power and increased utilization of glucose confirming our in vivo mouse studies. Conversely, inhibition of ATP citrate lyase during oncometabolic stress via D-2-hydroxyglutarate improved cardiac contractile function via redirection of Krebs cycle flux and provision of ATP levels. Together these data demonstrate that ATP citrate lyase regulates oxidative metabolism and structural remodeling in the heart and creates a targetable metabolic liability during cancer.