{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:53:51Z","timestamp":1791572031787,"version":"4.3.4"},"posted":{"date-parts":[[2025,2,8]]},"group-title":"Physiology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T00:00:00Z","timestamp":1738972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cardiometabolic diseases, such as obesity and hypertension, negatively impact several organs simultaneously [1]. These adverse outcomes may result from a single stress that disrupts similar metabolic processes in different tissues, or from specific signals that communicate damage from one organ to another. Recent systems biology studies in cardiometabolic heart failure with preserved ejection fraction (HFpEF) have identified unidirectional liver-to-heart signaling pathways that modulate cardiac inflammation and fibrosis [2, 3]. These pathways are controlled by liver-secreted factors that govern cardiac disease progression, supporting a growing paradigm whereby liver dysfunction drives disease in the heart [4]. Despite increased recognition of the heart as a secretory organ [5], its capacity to regulate metabolic processes in other tissues remains uncertain. Here, we identify Gcn5l1 as a heart-specific factor required to protect from systemic metabolic dysfunction in cardiometabolic HFpEF. Along with exacerbated cardiac dysfunction, cardiomyocyte-restricted Gcn5l1 deletion promoted obesity, systemic insulin resistance, and hepatic lipid accumulation in a mouse model of HFpEF. Integrated multiomic analyses showed that deletion of Gcn5l1 in cardiomyocytes disrupted Angptl3-regulated lipase activity across heart and liver, resulting in cholesterol-mediated liver steatosis. These changes were blocked by inhibiting Angptl3 using a clinically-approved monoclonal antibody. Our results demonstrate that heart-to-liver crosstalk pathways exist in HFpEF, and identify the heart as a source of systemic pathological signaling in cardiometabolic disease.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"636634v4_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.05.636634","type":"posted-content","created":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T21:05:31Z","timestamp":1739048731000},"source":"Crossref","is-referenced-by-count":0,"title":["Gcn5l1 governs heart-to-liver crosstalk in cardiometabolic heart failure by modulating cholesterol metabolism"],"prefix":"10.64898","author":[{"given":"Paramesha","family":"Bugga","sequence":"first","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bellina A.S.","family":"Mushala","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Stoner","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet R.","family":"Manning","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha","family":"Bhattarai","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Sharifi-Sanjani","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Vandevender","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja G.R.","family":"Mooli","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadeesh K.","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Sembrat","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, and University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-4937","authenticated-orcid":false,"given":"Brett A.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sruti S.","family":"Shiva","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Classical Hematology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra L.","family":"Happe","sequence":"additional","affiliation":[{"name":"Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Mullet","sequence":"additional","affiliation":[{"name":"Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy L.","family":"Gelhaus","sequence":"additional","affiliation":[{"name":"Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Jurczak","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Scott","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100911300812000_2025.02.05.636634v4.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.062874"},{"key":"2026100911300812000_2025.02.05.636634v4.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0910"},{"key":"2026100911300812000_2025.02.05.636634v4.3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.324829"},{"key":"2026100911300812000_2025.02.05.636634v4.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-026-01257-z"},{"key":"2026100911300812000_2025.02.05.636634v4.5","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac759"},{"key":"2026100911300812000_2025.02.05.636634v4.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.01.049"},{"key":"2026100911300812000_2025.02.05.636634v4.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.03.393"},{"key":"2026100911300812000_2025.02.05.636634v4.8","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3567"},{"key":"2026100911300812000_2025.02.05.636634v4.9","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00752.2016"},{"key":"2026100911300812000_2025.02.05.636634v4.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC118.005462"},{"key":"2026100911300812000_2025.02.05.636634v4.11","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03782-0"},{"key":"2026100911300812000_2025.02.05.636634v4.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1100-z"},{"key":"2026100911300812000_2025.02.05.636634v4.13","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.065866"},{"key":"2026100911300812000_2025.02.05.636634v4.14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.050498"},{"key":"2026100911300812000_2025.02.05.636634v4.15","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R200015-JLR200"},{"key":"2026100911300812000_2025.02.05.636634v4.16","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba4448"},{"key":"2026100911300812000_2025.02.05.636634v4.17","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001423"},{"key":"2026100911300812000_2025.02.05.636634v4.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2004215"},{"key":"2026100911300812000_2025.02.05.636634v4.19","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14.10.1345"},{"key":"2026100911300812000_2025.02.05.636634v4.20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59701"},{"key":"2026100911300812000_2025.02.05.636634v4.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.029"},{"key":"2026100911300812000_2025.02.05.636634v4.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1409427111"},{"key":"2026100911300812000_2025.02.05.636634v4.23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.037216"},{"key":"2026100911300812000_2025.02.05.636634v4.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44680-3"},{"key":"2026100911300812000_2025.02.05.636634v4.25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107823200"},{"key":"2026100911300812000_2025.02.05.636634v4.26","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M065011"},{"key":"2026100911300812000_2025.02.05.636634v4.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.11.018"},{"key":"2026100911300812000_2025.02.05.636634v4.28","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.027216"},{"key":"2026100911300812000_2025.02.05.636634v4.29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.112.972828"},{"key":"2026100911300812000_2025.02.05.636634v4.30","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae868"},{"key":"2026100911300812000_2025.02.05.636634v4.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2024.100869"},{"key":"2026100911300812000_2025.02.05.636634v4.32","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58069"},{"key":"2026100911300812000_2025.02.05.636634v4.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2026.02.024"},{"key":"2026100911300812000_2025.02.05.636634v4.34","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01273-4"},{"key":"2026100911300812000_2025.02.05.636634v4.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2019.02.009"},{"key":"2026100911300812000_2025.02.05.636634v4.36","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20230302"},{"key":"2026100911300812000_2025.02.05.636634v4.37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.050498"},{"key":"2026100911300812000_2025.02.05.636634v4.38","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba4448"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.02.05.636634","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:30:17Z","timestamp":1791570617000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.02.05.636634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,8]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1101\/2025.02.05.636634","relation":{},"subject":[],"published":{"date-parts":[[2025,2,8]]},"subtype":"preprint"}}