{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T02:31:45Z","timestamp":1775788305897,"version":"3.50.1"},"posted":{"date-parts":[[2024,6,10]]},"group-title":"Molecular Biology","reference-count":53,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found\n                    <jats:italic>ACLY<\/jats:italic>\n                    gene expression is reduced; however the impact this might have on cardiac function and\/or metabolism has not been previously studied. As new ACLY inhibitors are in development for cancer and other disorders, such understanding has added importance.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Cardiomyocytes,\n                    <jats:italic>ex-vivo<\/jats:italic>\n                    beating hearts, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    hearts with ACLY inhibited by selective pharmacologic (BMS303141, ACLYi) or genetic suppression, were studied. Regulation of ACLY gene\/protein expression, and effects of ACLYi on function, cytotoxicity, tricarboxylic acid (TCA)-cycle metabolism, and redox and NAD+\/NADH balance were assessed. Mice with cardiac ACLY knockdown induced by AAV9-\n                    <jats:italic>acly-<\/jats:italic>\n                    shRNA or cardiomyocyte tamoxifen-inducible\n                    <jats:italic>Acly<\/jats:italic>\n                    knockdown were studied.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Acly<\/jats:italic>\n                    gene expression was reduced more in obese patients with heart failure and preserved EF (HFpEF) than HF with reduced EF.\n                    <jats:italic>In vivo<\/jats:italic>\n                    pressure-overload and\n                    <jats:italic>in vitro<\/jats:italic>\n                    hormonal stress increased ACLY protein expression, whereas it declined upon fatty-acid exposure. Acute ACLYi (1-hr) dose-dependently induced cytotoxicity in adult and neonatal cardiomyocytes, and caused substantial reduction of systolic and diastolic function in myocytes and\n                    <jats:italic>ex-vivo<\/jats:italic>\n                    beating hearts. In the latter, ATP\/ADP ratio also fell and lactate increased. U\n                    <jats:sub>13<\/jats:sub>\n                    C-glucose tracing revealed an ACLY-dependent TCA-bypass circuit in myocytes, where citrate generated in mitochondria is transported to the cytosol, metabolized by ACLY and then converted to malate to re-enter mitochondria, bypassing several NADH-generating steps. ACLYi lowered NAD+\/NADH ratio and restoring this balance ameliorated cardiomyocyte toxicity. Oxidative stress was undetected with ACLYi. Adult hearts following 8-weeks of reduced cardiac and\/or cardiomyocyte ACLY downregulation exhibited ventricular dilation and reduced function that was prevented by NAD augmentation. Cardiac dysfunction from ACLY knockdown was worse in hearts subjected to sustained pressure-overload, supporting a role in stress responses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ACLY supports normal cardiac function through maintenance of the NAD+\/NADH balance and is upregulated by hemodynamic and hormonal stress, but depressed by lipid excess. ACLY levels are most reduced in human HFpEF with obesity potentially worsening cardio-metabolic reserve.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.09.598152","type":"posted-content","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T18:10:15Z","timestamp":1718043015000},"source":"Crossref","is-referenced-by-count":4,"title":["ATP Citrate Lyase Supports Cardiac Function and NAD+\/NADH Balance And Is Depressed in Human Heart Failure"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-1587","authenticated-orcid":false,"given":"Mariam","family":"Meddeb","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3021-3894","authenticated-orcid":false,"given":"Navid","family":"Koleini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seungho","family":"Jun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5728-7848","authenticated-orcid":false,"given":"Mohammad","family":"Keykhaei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-2648","authenticated-orcid":false,"given":"Farnaz","family":"Farshidfar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seoyoung","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-7994","authenticated-orcid":false,"given":"Gizem","family":"Keceli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7011-997X","authenticated-orcid":false,"given":"Nazareno","family":"Paolocci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kavita","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika L.","family":"Pearce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-2299","authenticated-orcid":false,"given":"David A.","family":"Kass","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024061321301390000_2024.06.09.598152v1.1","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/S0140-6736(23)02750-2","article-title":"Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults","volume":"403","year":"2024","journal-title":"Lancet"},{"key":"2024061321301390000_2024.06.09.598152v1.2","doi-asserted-by":"publisher","DOI":"10.5888\/pcd14.160287"},{"key":"2024061321301390000_2024.06.09.598152v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30054-X"},{"key":"2024061321301390000_2024.06.09.598152v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1614362"},{"key":"2024061321301390000_2024.06.09.598152v1.5","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000111245.75752.C6"},{"key":"2024061321301390000_2024.06.09.598152v1.6","doi-asserted-by":"crossref","unstructured":"Ndumele CE , Matsushita K , Lazo M , Bello N , Blumenthal RS , Gerstenblith G , Nambi V , Ballantyne CM , Solomon SD , Selvin E , Folsom AR and Coresh J . 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