{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T08:26:31Z","timestamp":1786782391720,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,13]]},"group-title":"Cell Biology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL155107"],"award-info":[{"award-number":["R01 HL155107"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL166137"],"award-info":[{"award-number":["R01 HL166137"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["MERIT grant 1185447"],"award-info":[{"award-number":["MERIT grant 1185447"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"name":"RePO4EU","award":["EU HorizonHealth grant 10157619"],"award-info":[{"award-number":["EU HorizonHealth grant 10157619"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The role of 2-hydroxyglutarate in lipid metabolism is currently unknown. Here we show that 2HG redistributes the partitioning of fatty acids into triglyceride storage and away from membrane phospholipid synthesis, mitochondrial oxidation, and lipotoxic intermediates. In primary human cardiac and vascular cells, both enantiomers, D2HG and L2HG, expanded triglyceride stores and lipid droplets while selectively depleting phosphatidylethanolamine, with L2HG acting more potently than D2HG despite lower intracellular accumulation. Mechanistically, L2HG increases DGAT-dependent triglyceride synthesis, slows triglyceride turnover, and constrains the ethanolamine branch of the Kennedy pathway. This response limits fatty acid oxidation, long-chain acylcarnitine accumulation, and lipid peroxidation independently of pseudohypoxic transcription or canonical lipid storage regulators, while also remodeling the phosphoproteome and redox proteome. L2HG accumulation induces hypertriglyceridemia in mice, redistributes the acyl chain composition of cardiac triglycerides, and limits ischemia-induced acylcarnitine accumulation in the heart, mirroring a positive association between circulating 2HG and triglycerides in humans. Thus, 2HG expands metabolic flexibility from whether fatty acids are used as fuel to how that fuel is allocated among storage, membrane synthesis, and oxidation.<\/jats:p>","DOI":"10.64898\/2026.08.12.744465","type":"posted-content","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T23:35:11Z","timestamp":1786664111000},"source":"Crossref","is-referenced-by-count":0,"title":["2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9693-4779","authenticated-orcid":false,"given":"Niv","family":"Vigder","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Chandra","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishith","family":"Shrimali","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Tumanov","sequence":"additional","affiliation":[{"name":"OmniFlux, Newton, NSW, Australia"},{"name":"University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Elgart","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huamei","family":"He","sequence":"additional","affiliation":[{"name":"Boston University Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Mulhern","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram P.","family":"Chakrabarty","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7208-3886","authenticated-orcid":false,"given":"Navdeep S.","family":"Chandel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Cordwell","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Science, Faculty of Science, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4291-413X","authenticated-orcid":false,"given":"Jo\u00e3o A.","family":"Paulo","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Loscalzo","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081500550714000_2026.08.12.744465v1.1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-200306000-00008"},{"key":"2026081500550714000_2026.08.12.744465v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01364-4"},{"key":"2026081500550714000_2026.08.12.744465v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0630588100"},{"key":"2026081500550714000_2026.08.12.744465v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0085-z"},{"key":"2026081500550714000_2026.08.12.744465v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.06.003"},{"key":"2026081500550714000_2026.08.12.744465v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.09.020"},{"key":"2026081500550714000_2026.08.12.744465v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.04.015"},{"key":"2026081500550714000_2026.08.12.744465v1.8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100616-060608"},{"key":"2026081500550714000_2026.08.12.744465v1.9","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.trecan.2017.12.005","article-title":"Metabolism, Activity, and Targeting of D- and L- 2-Hydroxyglutarates","volume":"4","year":"2018","journal-title":"Trends Cancer"},{"key":"2026081500550714000_2026.08.12.744465v1.10","doi-asserted-by":"crossref","first-page":"651317","DOI":"10.3389\/fcell.2021.651317","article-title":"The Roles of 2-Hydroxyglutarate","volume":"9","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2026081500550714000_2026.08.12.744465v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/nature08617"},{"key":"2026081500550714000_2026.08.12.744465v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.01.020"},{"key":"2026081500550714000_2026.08.12.744465v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.12.014"},{"key":"2026081500550714000_2026.08.12.744465v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2011.43"},{"key":"2026081500550714000_2026.08.12.744465v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nature10860"},{"key":"2026081500550714000_2026.08.12.744465v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.06.021"},{"key":"2026081500550714000_2026.08.12.744465v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.06.023"},{"key":"2026081500550714000_2026.08.12.744465v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2307"},{"key":"2026081500550714000_2026.08.12.744465v1.19","doi-asserted-by":"crossref","unstructured":"Chakrabarty, R. P. et al. Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite. Nature (2026).","DOI":"10.1038\/s41586-026-10564-x"},{"key":"2026081500550714000_2026.08.12.744465v1.20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0696"},{"key":"2026081500550714000_2026.08.12.744465v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nature20165"},{"key":"2026081500550714000_2026.08.12.744465v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404840101"},{"key":"2026081500550714000_2026.08.12.744465v1.23","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/s41557-026-02093-x","article-title":"Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates","volume":"18","year":"2026","journal-title":"Nat Chem"},{"key":"2026081500550714000_2026.08.12.744465v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02553-7"},{"key":"2026081500550714000_2026.08.12.744465v1.25","doi-asserted-by":"publisher","DOI":"10.1021\/jm7013887"},{"key":"2026081500550714000_2026.08.12.744465v1.26","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01006"},{"key":"2026081500550714000_2026.08.12.744465v1.27","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1038\/s42255-024-01150-4","article-title":"Branched-chain \u03b1-ketoacids aerobically activate HIF1\u03b1 signalling in vascular cells","volume":"6","year":"2024","journal-title":"Nat Metab"},{"key":"2026081500550714000_2026.08.12.744465v1.28","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201402104"},{"key":"2026081500550714000_2026.08.12.744465v1.29","doi-asserted-by":"publisher","DOI":"10.1021\/cr200084z"},{"key":"2026081500550714000_2026.08.12.744465v1.30","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1161\/CIRCRESAHA.122.321227","article-title":"L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling","volume":"131","year":"2022","journal-title":"Circ Res"},{"key":"2026081500550714000_2026.08.12.744465v1.31","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160164"},{"key":"2026081500550714000_2026.08.12.744465v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/nature07976"},{"key":"2026081500550714000_2026.08.12.744465v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2439"},{"key":"2026081500550714000_2026.08.12.744465v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.01.029"},{"key":"2026081500550714000_2026.08.12.744465v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.012"},{"key":"2026081500550714000_2026.08.12.744465v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.07.013"},{"key":"2026081500550714000_2026.08.12.744465v1.37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108764"},{"key":"2026081500550714000_2026.08.12.744465v1.38","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0021-9258(18)81295-9","article-title":"Studies on the mechnism of activation of acetyl coenzyme A carboxylase by citrate","volume":"238","year":"1963","journal-title":"J Biol Chem"},{"key":"2026081500550714000_2026.08.12.744465v1.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164097"},{"key":"2026081500550714000_2026.08.12.744465v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature02488"},{"key":"2026081500550714000_2026.08.12.744465v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.08.040"},{"key":"2026081500550714000_2026.08.12.744465v1.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700899104"},{"key":"2026081500550714000_2026.08.12.744465v1.43","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26399"},{"key":"2026081500550714000_2026.08.12.744465v1.44","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-1507"},{"key":"2026081500550714000_2026.08.12.744465v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20752-6"},{"key":"2026081500550714000_2026.08.12.744465v1.46","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40170-018-0178-3","article-title":"Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner","volume":"6","year":"2018","journal-title":"Cancer Metab"},{"key":"2026081500550714000_2026.08.12.744465v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.056"},{"key":"2026081500550714000_2026.08.12.744465v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.021"},{"key":"2026081500550714000_2026.08.12.744465v1.49","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2009"},{"key":"2026081500550714000_2026.08.12.744465v1.50","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/s42255-025-01332-8","article-title":"2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction","volume":"7","year":"2025","journal-title":"Nat Metab"},{"key":"2026081500550714000_2026.08.12.744465v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.76"},{"key":"2026081500550714000_2026.08.12.744465v1.52","doi-asserted-by":"crossref","first-page":"e0240764","DOI":"10.1371\/journal.pone.0240764","article-title":"Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions","volume":"16","year":"2021","journal-title":"PLoS One"},{"key":"2026081500550714000_2026.08.12.744465v1.53","doi-asserted-by":"publisher","DOI":"10.1001\/jama.299.10.1139"},{"key":"2026081500550714000_2026.08.12.744465v1.54","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1007\/s00125-016-4051-z","article-title":"Effects of exercise training alone vs a combined exercise and nutritional lifestyle intervention on glucose homeostasis in prediabetic individuals: a randomised controlled trial","volume":"59","year":"2016","journal-title":"Diabetologia"},{"key":"2026081500550714000_2026.08.12.744465v1.55","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.310307"},{"key":"2026081500550714000_2026.08.12.744465v1.56","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-1549"},{"key":"2026081500550714000_2026.08.12.744465v1.57","first-page":"80r","article-title":"Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss","volume":"3","year":"2011","journal-title":"Sci Transl Med"},{"key":"2026081500550714000_2026.08.12.744465v1.58","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1038\/oby.2009.473","article-title":"Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding","volume":"18","year":"2010","journal-title":"Obesity (Silver Spring"},{"key":"2026081500550714000_2026.08.12.744465v1.59","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1176"},{"key":"2026081500550714000_2026.08.12.744465v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.soard.2017.09.004"},{"key":"2026081500550714000_2026.08.12.744465v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1011"},{"key":"2026081500550714000_2026.08.12.744465v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-416618-9.00020-0"},{"key":"2026081500550714000_2026.08.12.744465v1.63","doi-asserted-by":"crossref","first-page":"vbac016","DOI":"10.1093\/bioadv\/vbac016","article-title":"decoupleR: ensemble of computational methods to infer biological activities from omics data","volume":"2","year":"2022","journal-title":"Bioinform Adv"},{"key":"2026081500550714000_2026.08.12.744465v1.64","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad841"},{"key":"2026081500550714000_2026.08.12.744465v1.65","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.8b00217"},{"key":"2026081500550714000_2026.08.12.744465v1.66","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.2c00806"},{"key":"2026081500550714000_2026.08.12.744465v1.67","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2377"},{"key":"2026081500550714000_2026.08.12.744465v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1240"},{"key":"2026081500550714000_2026.08.12.744465v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.001"},{"key":"2026081500550714000_2026.08.12.744465v1.70","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-444-9_5"},{"key":"2026081500550714000_2026.08.12.744465v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1019"},{"key":"2026081500550714000_2026.08.12.744465v1.72","doi-asserted-by":"publisher","DOI":"10.1021\/ac301572t"},{"key":"2026081500550714000_2026.08.12.744465v1.73","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-022-05575-3"},{"key":"2026081500550714000_2026.08.12.744465v1.74","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07407-y"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.12.744465","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T07:55:18Z","timestamp":1786780518000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.12.744465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":74,"URL":"https:\/\/doi.org\/10.64898\/2026.08.12.744465","relation":{},"subject":[],"published":{"date-parts":[[2026,8,13]]},"subtype":"preprint"}}