{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:53:54Z","timestamp":1791086034858,"version":"4.1.0"},"posted":{"date-parts":[[2026,6,11]]},"reference-count":85,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Excess fatty acids can disrupt membrane and organelle function. Cells buffer fatty acid toxicity by synthesizing and storing triglycerides (TGs) in lipid droplets, but their capacity for TG storage is limited. Here, we impaired TG synthesis in hepatocytes and identified adaptive pathways that restore homeostasis during lipid overload. Transcription responds by activating fatty acid oxidation through peroxisome proliferator-activated receptors, and by suppressing synthesis of new, unsaturated fatty acids through sterol regulatory element-binding protein 1 (SREBP1). Mechanistically, SREBP1 appears to respond to changes in ER membrane fluidity. These findings reveal a homeostatic system monitoring and maintaining the ER membrane, coordinating fatty acid synthesis and oxidation, a finding with broad implications for understanding lipid physiology and developing TG synthesis inhibitors for treating fatty liver disease.<\/jats:p>","DOI":"10.64898\/2026.06.10.731409","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T10:40:11Z","timestamp":1781174411000},"source":"Crossref","is-referenced-by-count":1,"title":["A membrane homeostatic response to lipid overload coordinates fatty acid metabolism"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8869-0443","authenticated-orcid":false,"given":"Xiaojun","family":"Xiang","sequence":"first","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Howard Hughes Medical Institute, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohannes A.","family":"Ambaw","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozlem","family":"Tok","sequence":"additional","affiliation":[{"name":"Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-chun","family":"Tang","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Howard Hughes Medical Institute, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arda","family":"Mizrak","sequence":"additional","affiliation":[{"name":"Cell Biology Department, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Cohen-Abeles","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Robert V.","family":"Farese","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1442-1327","authenticated-orcid":false,"given":"Tobias C.","family":"Walther","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Howard Hughes Medical Institute, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070906100671000_2026.06.10.731409v2.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.23.10878"},{"key":"2026070906100671000_2026.06.10.731409v2.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.4.1784"},{"key":"2026070906100671000_2026.06.10.731409v2.3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23719"},{"key":"2026070906100671000_2026.06.10.731409v2.4","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201100671"},{"key":"2026070906100671000_2026.06.10.731409v2.5","doi-asserted-by":"crossref","first-page":"119053","DOI":"10.1016\/j.atherosclerosis.2024.119053","article-title":"Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"400","year":"2025","journal-title":"Atherosclerosis"},{"key":"2026070906100671000_2026.06.10.731409v2.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0630588100"},{"key":"2026070906100671000_2026.06.10.731409v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.01.036"},{"key":"2026070906100671000_2026.06.10.731409v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.012"},{"key":"2026070906100671000_2026.06.10.731409v2.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13018"},{"key":"2026070906100671000_2026.06.10.731409v2.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106219200"},{"key":"2026070906100671000_2026.06.10.731409v2.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2007.00689.x"},{"key":"2026070906100671000_2026.06.10.731409v2.12","doi-asserted-by":"crossref","unstructured":"Farese, R. V., Jr. & Walther, T. C . Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum. Cold Spring Harb Perspect Biol 15 (2023).","DOI":"10.1101\/cshperspect.a041246"},{"key":"2026070906100671000_2026.06.10.731409v2.13","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22980"},{"key":"2026070906100671000_2026.06.10.731409v2.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6223"},{"key":"2026070906100671000_2026.06.10.731409v2.15","doi-asserted-by":"publisher","DOI":"10.2337\/db06-0016"},{"key":"2026070906100671000_2026.06.10.731409v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90690-R"},{"key":"2026070906100671000_2026.06.10.731409v2.17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215593"},{"key":"2026070906100671000_2026.06.10.731409v2.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.05.005"},{"key":"2026070906100671000_2026.06.10.731409v2.19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704213200"},{"key":"2026070906100671000_2026.06.10.731409v2.20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20783"},{"key":"2026070906100671000_2026.06.10.731409v2.21","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30765"},{"key":"2026070906100671000_2026.06.10.731409v2.22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007273200"},{"key":"2026070906100671000_2026.06.10.731409v2.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111138698"},{"key":"2026070906100671000_2026.06.10.731409v2.24","doi-asserted-by":"crossref","first-page":"e2409262121","DOI":"10.1073\/pnas.2409262121","article-title":"Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids","volume":"121","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026070906100671000_2026.06.10.731409v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.01.011"},{"key":"2026070906100671000_2026.06.10.731409v2.26","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90234-8"},{"key":"2026070906100671000_2026.06.10.731409v2.27","doi-asserted-by":"crossref","unstructured":"Costa-Mattioli, M. & Walter, P . The integrated stress response: From mechanism to disease. Science 368 (2020).","DOI":"10.1126\/science.aat5314"},{"key":"2026070906100671000_2026.06.10.731409v2.28","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"2026070906100671000_2026.06.10.731409v2.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.10.006"},{"key":"2026070906100671000_2026.06.10.731409v2.30","doi-asserted-by":"publisher","DOI":"10.1038\/75651"},{"key":"2026070906100671000_2026.06.10.731409v2.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311000200"},{"key":"2026070906100671000_2026.06.10.731409v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41132-w"},{"key":"2026070906100671000_2026.06.10.731409v2.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.09.097"},{"key":"2026070906100671000_2026.06.10.731409v2.34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118951"},{"key":"2026070906100671000_2026.06.10.731409v2.35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0022-2275(20)30193-0","article-title":"Dual regulation of mouse \u03945- and \u03946-desaturase gene expression by SREBP-1 and PPAR\u03b1","volume":"43","year":"2002","journal-title":"Journal of Lipid Research"},{"key":"2026070906100671000_2026.06.10.731409v2.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52538-5"},{"key":"2026070906100671000_2026.06.10.731409v2.37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.8.4333"},{"key":"2026070906100671000_2026.06.10.731409v2.38","doi-asserted-by":"crossref","first-page":"E270","DOI":"10.1152\/ajpendo.2001.280.2.E270","article-title":"A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle","volume":"280","year":"2001","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2026070906100671000_2026.06.10.731409v2.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7473"},{"key":"2026070906100671000_2026.06.10.731409v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81304-5"},{"key":"2026070906100671000_2026.06.10.731409v2.41","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81668-2"},{"key":"2026070906100671000_2026.06.10.731409v2.42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1534923100"},{"key":"2026070906100671000_2026.06.10.731409v2.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000133"},{"key":"2026070906100671000_2026.06.10.731409v2.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.1477"},{"key":"2026070906100671000_2026.06.10.731409v2.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.04.010"},{"key":"2026070906100671000_2026.06.10.731409v2.46","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.4c00249"},{"key":"2026070906100671000_2026.06.10.731409v2.47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.6.3406"},{"key":"2026070906100671000_2026.06.10.731409v2.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.9.4312"},{"key":"2026070906100671000_2026.06.10.731409v2.49","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M020156"},{"key":"2026070906100671000_2026.06.10.731409v2.50","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M093112"},{"key":"2026070906100671000_2026.06.10.731409v2.51","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/aps.2010.104","article-title":"Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight gain, hyperlipidemia, and hepatic steatosis in db\/db mice","volume":"31","year":"2010","journal-title":"Acta Pharmacol Sin"},{"key":"2026070906100671000_2026.06.10.731409v2.52","doi-asserted-by":"crossref","unstructured":"Chitraju, C. et al. Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity. Elife 12 (2023).","DOI":"10.7554\/eLife.88049.3"},{"key":"2026070906100671000_2026.06.10.731409v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108348"},{"key":"2026070906100671000_2026.06.10.731409v2.54","doi-asserted-by":"crossref","unstructured":"Sharma, A. K. et al. DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function. Cell Metab (2026).","DOI":"10.1016\/j.cmet.2026.04.007"},{"key":"2026070906100671000_2026.06.10.731409v2.55","doi-asserted-by":"crossref","unstructured":"Luukkonen, P. K. , et al. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight 4 (2019).","DOI":"10.1172\/jci.insight.127902"},{"key":"2026070906100671000_2026.06.10.731409v2.56","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00591-9"},{"key":"2026070906100671000_2026.06.10.731409v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80213-5"},{"key":"2026070906100671000_2026.06.10.731409v2.58","doi-asserted-by":"publisher","DOI":"10.1101\/gad.844900"},{"key":"2026070906100671000_2026.06.10.731409v2.59","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071124"},{"key":"2026070906100671000_2026.06.10.731409v2.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.09.045"},{"key":"2026070906100671000_2026.06.10.731409v2.61","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93616"},{"key":"2026070906100671000_2026.06.10.731409v2.62","doi-asserted-by":"crossref","first-page":"101495","DOI":"10.1016\/j.isci.2020.101495","article-title":"Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids","volume":"23","year":"2020","journal-title":"iScience"},{"key":"2026070906100671000_2026.06.10.731409v2.63","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00080-5"},{"key":"2026070906100671000_2026.06.10.731409v2.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.05.015"},{"key":"2026070906100671000_2026.06.10.731409v2.65","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1021\/acscentsci.5c00606","article-title":"Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking","volume":"11","year":"2025","journal-title":"ACS Cent Sci"},{"key":"2026070906100671000_2026.06.10.731409v2.66","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.chembiol.2025.12.006","article-title":"1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway","volume":"33","year":"2026","journal-title":"Cell Chem Biol"},{"key":"2026070906100671000_2026.06.10.731409v2.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.019"},{"key":"2026070906100671000_2026.06.10.731409v2.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.10.008"},{"key":"2026070906100671000_2026.06.10.731409v2.69","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20091283"},{"key":"2026070906100671000_2026.06.10.731409v2.70","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)74726-2"},{"key":"2026070906100671000_2026.06.10.731409v2.71","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-0071"},{"key":"2026070906100671000_2026.06.10.731409v2.72","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1172\/JCI89444","article-title":"Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance","volume":"127","year":"2017","journal-title":"J Clin Invest"},{"key":"2026070906100671000_2026.06.10.731409v2.73","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.11.049"},{"key":"2026070906100671000_2026.06.10.731409v2.74","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200523621"},{"key":"2026070906100671000_2026.06.10.731409v2.75","doi-asserted-by":"crossref","unstructured":"Amin, N. B. et al. Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis. Sci Transl Med 11 (2019).","DOI":"10.1126\/scitranslmed.aav9701"},{"key":"2026070906100671000_2026.06.10.731409v2.76","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01489-1"},{"key":"2026070906100671000_2026.06.10.731409v2.77","doi-asserted-by":"crossref","first-page":"15000","DOI":"10.1021\/acs.jmedchem.2c01200","article-title":"Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis","volume":"65","year":"2022","journal-title":"J Med Chem"},{"key":"2026070906100671000_2026.06.10.731409v2.78","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S0140-6736(25)00979-1","article-title":"Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","volume":"406","year":"2025","journal-title":"Lancet"},{"key":"2026070906100671000_2026.06.10.731409v2.79","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026070906100671000_2026.06.10.731409v2.80","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"2026070906100671000_2026.06.10.731409v2.81","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"2026070906100671000_2026.06.10.731409v2.82","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D700041-JLR200"},{"key":"2026070906100671000_2026.06.10.731409v2.83","doi-asserted-by":"crossref","first-page":"e70631","DOI":"10.1002\/alz.70631","article-title":"Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations","volume":"21","year":"2025","journal-title":"Alzheimers Dement"},{"key":"2026070906100671000_2026.06.10.731409v2.84","doi-asserted-by":"crossref","unstructured":"Abdi, H. et al. LipidCruncher: an open-source platform for processing, visualizing, and analyzing lipidomic data. BMC Bioinformatics (2026).","DOI":"10.1186\/s12859-026-06483-3"},{"key":"2026070906100671000_2026.06.10.731409v2.85","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.419"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.10.731409","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:10:16Z","timestamp":1783602616000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.10.731409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":85,"URL":"https:\/\/doi.org\/10.64898\/2026.06.10.731409","relation":{},"subject":[],"published":{"date-parts":[[2026,6,11]]},"subtype":"preprint"}}