ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart
Authored by
Shijie Liu, Seth T. Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Ian K. Williamson, Janet Pham, Angela Davidian, Radhika Khanna, Benjamin D. Gould, Rebecca Salazar, Heidi Vitrac, An Dinh, Evan C. Lien, Francisca N. de L. Vitorino, Joanna M. Gongora, Sara A. Martinez, Czer S. C. Lawrence, Evan P. Kransdorf, David Leffer, Blake Hanson, Benjamin A. Garcia,
Matthew G. Vander Heiden, Philip L. Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms,
James F. Martin, and
Anja Karlstaedt
- Posted
- Server
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bioRxiv
Background
Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL,Acly), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear.
Methods
We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivateAclyin cardiomyocytes of MyH6-Cas9 mice.In vivo,positron emission tomography andex vivostable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. 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
Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation.Ex vivoisotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate.
Conclusions
This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.
