{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T09:03:26Z","timestamp":1793091806775,"version":"4.5.0"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      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,\n                      <jats:italic toggle=\"yes\">Acly<\/jats:italic>\n                      ), which produces acetyl\u2013coenzyme 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">Acly<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Acly<\/jats:italic>\n                      knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry\u2013based 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      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. Using CRISPR\/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry\u2013based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac\n                      <jats:italic toggle=\"yes\">Idh1<\/jats:italic>\n                      deletion improved cardiac function and energy provision, reducing YAP phosphorylation and restoring downstream YAP signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.076453","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T18:00:22Z","timestamp":1784570422000},"page":"223-239","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling"],"prefix":"10.1161","volume":"154","author":[{"given":"Shijie","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas Heart Institute, Houston, TX (S.L., J.F.M.)."},{"name":"Department of Molecular Cardiovascular Biology, Cincinnati Children\u2019s Hospital Medical Center, OH (S.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8647-0975","authenticated-orcid":true,"given":"Seth T.","family":"Gammon","sequence":"additional","affiliation":[{"name":"Department of Cancer Systems Imaging (S.T.G., D.P.-W.), University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology (L.T., S.A.M., P.L.L.), University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6181-4027","authenticated-orcid":true,"given":"Yaqi","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, 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