Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling

作者：Shijie Liu, Seth T. Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Mahmoud H. Elbatreek, Adrian Arrieta, Ian K. Williamson, Rebecca L. Salazar, Janet Pham, Angela Davidian, Radhika Khanna Neicheril, Benjamin D. Gould, Heidi Vitrac, Alia Sadiq, An Q Dinh, Evan C. Lien, Francisca N. de Luna Vitorino, Joanna Gongora, Sara Martínez, Melanie T. Odenkirk, Anna K. Boatman, Jessie R. Chappel, L. Czer, E. Kransdorf, David J. Lefer, Blake Hanson, Benjamin A. Garcia, Erin Baker, Matthew G. Vander Heiden, Philip L. Lorenzi, Heinrich Taegtmeyer, David Piwnica‐Worms, James F. Martin, Anja Karlstaedt · 发表于：Circulation · 年份：2026 · DOI：10.1161/circulationaha.125.076453 · 被引用次数：1 · 研究领域：Cardiovascular Function and Risk Factors、Mitochondrial Function and Pathology、Metabolism and Genetic Disorders

BACKGROUND: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly ), which produces acetyl–coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated. METHODS: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate Acly in cardiomyocytes of Myh6-Cas9 mice. In vivo positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to Acly knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry–based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. RESULTS: We observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Us...