{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:46:37Z","timestamp":1768527997683,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,11]]},"group-title":"Cell Biology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01EY035683"],"award-info":[{"award-number":["R01EY035683"]}]},{"name":"NIH","award":["R01EY011766"],"award-info":[{"award-number":["R01EY011766"]}]},{"name":"NIH","award":["R01EY030500"],"award-info":[{"award-number":["R01EY030500"]}]},{"name":"NIH","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hypercholesterolemia and excessive cholesterol ester (CE) production have been linked to chronic inflammation and vascular dysfunction during cardiovascular disease. Upregulation of AcylCoA:cholesterol acyltransferase 1 (ACAT1\/SOAT1), the enzyme responsible for retinal CE formation, has been implicated in pathological retinal neovascularization. Here we determine the role of this process in diabetic retinopathy (DR). Ins2\n                  <jats:sup>Akita<\/jats:sup>\n                  diabetic mice were treated with the specific ACAT1\/SOAT1 inhibitor K604 (10 mg\/Kg, i.p.) beginning at 10 weeks for 2 weeks or 8 months for 2 months. ACAT1\/SOAT1 expression and CE formation were assayed along with oxidative stress, inflammation, vascular pathology, and neuronal function. ACAT1\/SOAT1 expression was also assayed in human retinas and vitrectomy specimens. Retinas from early-stage Ins2\n                  <jats:sup>Akita<\/jats:sup>\n                  mice exhibited increases in CE deposition, superoxide production, and expression of ACAT1\/SOAT1, LDLR, TREM1, MCSF, and VEGF along with leukostasis, vascular leakage, acellular capillary formation, retinal ganglion cell loss, and impaired visual function. Late-stage increases in CE, ACAT1\/SOAT, oxidative stress, inflammation, and impaired visual function were also observed. These changes were significantly inhibited by K604 treatment. The protective effects were independent of changes in systemic glucose or body weight. Human retina and vitrectomy samples also showed increases in ACAT1\/SOAT1 and CE, respectively. Specific inhibition of ACAT1\/SOAT1 with K604 normalizes ACAT1\/SOAT1 expression and CE formation and prevents increases in oxidative stress and inflammation and preserves retinal structure and function in both early and late stages of DR. These findings identify ACAT1\/SOAT1 as a promising therapeutic target for both early intervention and later stage treatment of DR.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Inhibiting cholesterol esterification limits retinal neurovascular injury in diabetes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.09.681484","type":"posted-content","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:30:14Z","timestamp":1760196614000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel Role of AcylCoA:cholesterol acyltransferase 1 (ACAT1\/SOAT1) in Diabetic Retinopathy"],"prefix":"10.64898","author":[{"given":"Syed Adeel H.","family":"Zaidi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tahira","family":"Lemtalsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhimin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8914-6273","authenticated-orcid":false,"given":"Mai","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Porsche V.","family":"Sandow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven E.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. William","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0168-0354","authenticated-orcid":false,"given":"Ruth B.","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9441-3302","authenticated-orcid":false,"given":"Modesto A.","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025101507500595000_2025.10.09.681484v2.1","unstructured":"NEI, Projections for Diabetic Retinopathy (2010-2030-2050). https:\/\/nei.nih.gov\/eyedata\/diabetic#5, (2010)."},{"key":"2025101507500595000_2025.10.09.681484v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2003.12.001"},{"key":"2025101507500595000_2025.10.09.681484v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2009.06.003"},{"key":"2025101507500595000_2025.10.09.681484v2.4","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.10-6293"},{"key":"2025101507500595000_2025.10.09.681484v2.5","doi-asserted-by":"crossref","unstructured":"C. Altmann , M. H. H. Schmidt , The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int J Mol Sci 19, (2018).","DOI":"10.3390\/ijms19010110"},{"key":"2025101507500595000_2025.10.09.681484v2.6","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/j.survophthal.2022.07.008","article-title":"Role of inflammatory cells in pathophysiology and management of diabetic retinopathy","volume":"67","year":"2022","journal-title":"Surv Ophthalmol"},{"key":"2025101507500595000_2025.10.09.681484v2.7","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-010-1315-z"},{"key":"2025101507500595000_2025.10.09.681484v2.8","doi-asserted-by":"crossref","unstructured":"R. T. Atawia , K. L. Bunch , A. Y. Fouda , T. Lemtalsi , W. Eldahshan , Z. Xu , A. Saul , K. Elmasry , M. Al-Shabrawey , R. B. Caldwell , R. W. Caldwell , Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity. J Clin Med 9, (2020).","DOI":"10.3390\/jcm9020317"},{"key":"2025101507500595000_2025.10.09.681484v2.9","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/eye.2013.107","article-title":"Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature","volume":"27","year":"2013","journal-title":"Eye (Lond)"},{"key":"2025101507500595000_2025.10.09.681484v2.10","doi-asserted-by":"publisher","DOI":"10.1001\/archophthalmol.2010.362"},{"key":"2025101507500595000_2025.10.09.681484v2.11","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.jcjd.2020.10.009","article-title":"Diabetic Retinopathy: Important Biochemical Alterations and the Main Treatment Strategies","volume":"45","year":"2021","journal-title":"Can J Diabetes"},{"key":"2025101507500595000_2025.10.09.681484v2.12","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2013.10.121"},{"key":"2025101507500595000_2025.10.09.681484v2.13","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201910473"},{"key":"2025101507500595000_2025.10.09.681484v2.14","doi-asserted-by":"crossref","first-page":"100017","DOI":"10.1194\/jlr.TR120000981","article-title":"Lipid metabolism dysregulation in diabetic retinopathy","volume":"62","year":"2021","journal-title":"J Lipid Res"},{"key":"2025101507500595000_2025.10.09.681484v2.15","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1440"},{"key":"2025101507500595000_2025.10.09.681484v2.16","unstructured":"J. Y. Yu , T. J. Lyons , Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina. J Clin Exp Ophthalmol 4, (2013)."},{"key":"2025101507500595000_2025.10.09.681484v2.17","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.312617"},{"key":"2025101507500595000_2025.10.09.681484v2.18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12974-023-02700-5","article-title":"Role of acyl-coenzyme A: cholesterol transferase 1 (ACAT1) in retinal neovascularization","volume":"20","year":"2023","journal-title":"J Neuroinflammation"},{"key":"2025101507500595000_2025.10.09.681484v2.19","doi-asserted-by":"crossref","unstructured":"Q. Hai , J. D. Smith , Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era. Metabolites 11, (2021).","DOI":"10.3390\/metabo11080543"},{"key":"2025101507500595000_2025.10.09.681484v2.20","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.18.10.1568"},{"key":"2025101507500595000_2025.10.09.681484v2.21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.7150\/ijms.50893","article-title":"TREM-1 promoted apoptosis and inhibited autophagy in LPS-treated HK-2 cells through the NF-kappaB pathway","volume":"18","year":"2021","journal-title":"Int J Med Sci"},{"key":"2025101507500595000_2025.10.09.681484v2.22","first-page":"e38806","article-title":"Could TREM-1 be a novel marker in the diagnosis of fibromyalgia?","volume":"103","year":"2024","journal-title":"A cross-sectional study. Medicine (Baltimore)"},{"key":"2025101507500595000_2025.10.09.681484v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13151"},{"key":"2025101507500595000_2025.10.09.681484v2.24","doi-asserted-by":"crossref","first-page":"602252","DOI":"10.3389\/fendo.2020.602252","article-title":"From Inert Storage to Biological Activity-In Search of Identity for Oxidized Cholesteryl Esters","volume":"11","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025101507500595000_2025.10.09.681484v2.25","doi-asserted-by":"crossref","first-page":"e01112","DOI":"10.1016\/j.heliyon.2018.e01112","article-title":"Rapid and reliable identification of insulin 2 gene mutation in Akita diabetic mice by a tetra-primer-ARMS-PCR method","volume":"5","year":"2019","journal-title":"Heliyon"},{"key":"2025101507500595000_2025.10.09.681484v2.26","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41419-022-05196-8","article-title":"Targeting proliferative retinopathy: Arginase 1 limits vitreoretinal neovascularization and promotes angiogenic repair","volume":"13","year":"2022","journal-title":"Cell Death & Disease"},{"key":"2025101507500595000_2025.10.09.681484v2.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072277"},{"key":"2025101507500595000_2025.10.09.681484v2.28","doi-asserted-by":"crossref","first-page":"900640","DOI":"10.3389\/fcvm.2022.900640","article-title":"Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice","volume":"9","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"2025101507500595000_2025.10.09.681484v2.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084357"},{"key":"2025101507500595000_2025.10.09.681484v2.30","doi-asserted-by":"crossref","first-page":"113923","DOI":"10.1016\/j.expneurol.2021.113923","article-title":"Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury","volume":"348","year":"2022","journal-title":"Exp Neurol"},{"key":"2025101507500595000_2025.10.09.681484v2.31","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-3375"},{"key":"2025101507500595000_2025.10.09.681484v2.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173716"},{"key":"2025101507500595000_2025.10.09.681484v2.33","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.2009.953448"},{"key":"2025101507500595000_2025.10.09.681484v2.34","doi-asserted-by":"crossref","first-page":"e110604","DOI":"10.1371\/journal.pone.0110604","article-title":"Arginase 2 deficiency prevents oxidative stress and limits hyperoxia-induced retinal vascular degeneration","volume":"9","year":"2014","journal-title":"PLoS One"},{"key":"2025101507500595000_2025.10.09.681484v2.35","doi-asserted-by":"crossref","first-page":"e2483","DOI":"10.1038\/cddis.2016.295","article-title":"Arginase 2 promotes neurovascular degeneration during ischemia\/reperfusion injury","volume":"7","year":"2016","journal-title":"Cell Death Dis"},{"key":"2025101507500595000_2025.10.09.681484v2.36","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.82.12.1298"},{"key":"2025101507500595000_2025.10.09.681484v2.37","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3389\/fnins.2018.00970","article-title":"Retinal Neuroprotection From Optic Nerve Trauma by Deletion of Arginase 2","volume":"12","year":"2018","journal-title":"Front Neurosci"},{"key":"2025101507500595000_2025.10.09.681484v2.38","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/s41419-023-06180-6","article-title":"Calbindin 2-specific deletion of arginase 2 preserves visual function after optic nerve crush","volume":"14","year":"2023","journal-title":"Cell Death Dis"},{"key":"2025101507500595000_2025.10.09.681484v2.39","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.04-0541"},{"key":"2025101507500595000_2025.10.09.681484v2.40","doi-asserted-by":"publisher","DOI":"10.1017\/S0952523805225166"},{"key":"2025101507500595000_2025.10.09.681484v2.41","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41419-022-05196-8","article-title":"Targeting proliferative retinopathy: Arginase 1 limits vitreoretinal neovascularization and promotes angiogenic repair","volume":"13","year":"2022","journal-title":"Cell Death Dis"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.09.681484","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:45:51Z","timestamp":1768470351000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.09.681484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,11]]},"references-count":41,"URL":"https:\/\/doi.org\/10.1101\/2025.10.09.681484","relation":{},"subject":[],"published":{"date-parts":[[2025,10,11]]},"subtype":"preprint"}}