{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:37:01Z","timestamp":1768509421660,"version":"3.49.0"},"posted":{"date-parts":[[2023,11,8]]},"group-title":"Biochemistry","reference-count":51,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,11,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>In age-related macular degeneration (AMD) and Sorsby\u2019s fundus dystrophy (SFD), lipid-rich deposits known as drusen accumulate under the retinal pigment epithelium (RPE). Drusen may contribute to photoreceptor and RPE degeneration in AMD and SFD. We hypothesize that stimulating \u03b2-oxidation in RPE will reduce drusen accumulation. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate \u03b2-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, limits the accumulation of lipid deposits in cultured RPE cells.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We probed metabolism and cellular function in mouse RPE-choroid, human fetal- derived RPE cells, and induced pluripotent stem cell-derived RPE cells. We used\n                    <jats:sup>13<\/jats:sup>\n                    C6-glucose and\n                    <jats:sup>13<\/jats:sup>\n                    C16-palmitate to determine the effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism.\n                    <jats:sup>13<\/jats:sup>\n                    C labeling of metabolites in these pathways were analyzed using gas chromatography-linked mass spectrometry. We quantified ApoE and VEGF release using enzyme-linked immunosorbent assays. Immunostaining of sectioned RPE was used to visualize ApoE deposits. RPE function was assessed by measuring the trans-epithelial electrical resistance (TEER).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>ACC inhibition with Firsocostat increases fatty acid oxidation and remodels lipid composition, glycolytic metabolism, lipoprotein release, and enhances TEER. When human serum is used to induce sub-RPE lipoprotein accumulation, fewer lipoproteins accumulate with Firsocostat. In a culture model of Sorsby\u2019s fundus dystrophy, Firsocostat also stimulates fatty acid oxidation, improves morphology, and increases TEER.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Firsocostat remodels intracellular metabolism and improves RPE resilience to serum-induced lipid deposition. This effect of ACC inhibition suggests that it could be an effective strategy for diminishing drusen accumulation in the eyes of patients with AMD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.11.07.566117","type":"posted-content","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T22:55:11Z","timestamp":1699484111000},"source":"Crossref","is-referenced-by-count":0,"title":["Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4481-1839","authenticated-orcid":false,"given":"Daniel T.","family":"Hass","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4682-2711","authenticated-orcid":false,"given":"Kriti","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-2082","authenticated-orcid":false,"given":"Abbi","family":"Engel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah","family":"Horton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian M.","family":"Robbings","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rayne","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Sadilek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qitao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian A.","family":"Autterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason M.L.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer R.","family":"Chao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James B.","family":"Hurley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023111306000549000_2023.11.07.566117v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(13)70145-1"},{"key":"2023111306000549000_2023.11.07.566117v1.2","doi-asserted-by":"publisher","DOI":"10.1159\/000518822"},{"key":"2023111306000549000_2023.11.07.566117v1.3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.preteyeres.2016.04.008","article-title":"Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes","volume":"53","year":"2016","journal-title":"Prog Retin Eye Res"},{"key":"2023111306000549000_2023.11.07.566117v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010329"},{"key":"2023111306000549000_2023.11.07.566117v1.5","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2376"},{"key":"2023111306000549000_2023.11.07.566117v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2004.09.017"},{"issue":"7","key":"2023111306000549000_2023.11.07.566117v1.7","first-page":"1592","article-title":"The lipid composition of drusen, Bruch\u2019s membrane, and sclera by hot stage polarizing light microscopy","volume":"42","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"10","key":"2023111306000549000_2023.11.07.566117v1.8","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1016\/S0161-6420(92)31768-3","article-title":"Correlation between biochemical composition and fluorescein binding of deposits in Bruch\u2019s membrane","volume":"99","year":"1992","journal-title":"Ophthalmology"},{"key":"2023111306000549000_2023.11.07.566117v1.9","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-1446"},{"key":"2023111306000549000_2023.11.07.566117v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9394(00)00961-2"},{"key":"2023111306000549000_2023.11.07.566117v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63836-9"},{"key":"2023111306000549000_2023.11.07.566117v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2009.08.001"},{"key":"2023111306000549000_2023.11.07.566117v1.13","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2011-300344"},{"issue":"1","key":"2023111306000549000_2023.11.07.566117v1.14","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/jnr.24317","article-title":"Sorsby fundus dystrophy: Insights from the past and looking to the future","volume":"97","year":"2019","journal-title":"J Neurosci Res"},{"key":"2023111306000549000_2023.11.07.566117v1.15","doi-asserted-by":"crossref","unstructured":"Engel AL , Wang Y , Khuu TH , Worrall E , Manson MA , Lim RR , et al. Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium. Exp Eye Res. 2022;215:108899.","DOI":"10.1016\/j.exer.2021.108899"},{"key":"2023111306000549000_2023.11.07.566117v1.16","doi-asserted-by":"crossref","unstructured":"Curcio CA . Soft Drusen in Age-Related Macular Degeneration: Biology and Targeting Via the Oil Spill Strategies. Invest Ophthalmol Vis Sci. 2018;59(4):AMD160-AMD81.","DOI":"10.1167\/iovs.18-24882"},{"key":"2023111306000549000_2023.11.07.566117v1.17","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2021.0067"},{"key":"2023111306000549000_2023.11.07.566117v1.18","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ebiom.2016.01.033","article-title":"Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment","volume":"5","year":"2016","journal-title":"EBioMedicine"},{"key":"2023111306000549000_2023.11.07.566117v1.19","first-page":"2750","article-title":"Studies on the mechanism of fatty acid synthesis","volume":"237","year":"1962","journal-title":"XII. Acetyl coenzyme A carboxylase. J Biol Chem"},{"issue":"23","key":"2023111306000549000_2023.11.07.566117v1.20","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.1021\/ja01556a086","article-title":"A malonic acid derivative as an intermediate in fatty acid synthesis","volume":"80","year":"1958","journal-title":"J Am Chem Soc"},{"issue":"12","key":"2023111306000549000_2023.11.07.566117v1.21","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1016\/S0021-9258(17)34693-8","article-title":"Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA","volume":"253","year":"1978","journal-title":"J Biol Chem"},{"key":"2023111306000549000_2023.11.07.566117v1.22","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0022-2275(20)40302-5","article-title":"LONG-CHAIN CARNITINE ACYLTRANSFERASE AND THE ROLE OF ACYLCARNITINE DERIVATIVES IN THE CATALYTIC INCREASE OF FATTY ACID OXIDATION INDUCED BY CARNITINE","volume":"4","year":"1963","journal-title":"J Lipid Res"},{"key":"2023111306000549000_2023.11.07.566117v1.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520686113"},{"key":"2023111306000549000_2023.11.07.566117v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2018.04.042"},{"issue":"1","key":"2023111306000549000_2023.11.07.566117v1.25","doi-asserted-by":"crossref","first-page":"e0228212","DOI":"10.1371\/journal.pone.0228212","article-title":"Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis","volume":"15","year":"2020","journal-title":"PLoS One"},{"key":"2023111306000549000_2023.11.07.566117v1.26","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-056159"},{"key":"2023111306000549000_2023.11.07.566117v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2015.04.002"},{"key":"2023111306000549000_2023.11.07.566117v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts127"},{"key":"2023111306000549000_2023.11.07.566117v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-019-1627-x"},{"key":"2023111306000549000_2023.11.07.566117v1.30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.788422"},{"issue":"9","key":"2023111306000549000_2023.11.07.566117v1.31","first-page":"322","article-title":"Passonneau: A flexible system of enzymatic analysis","volume":"25","year":"1973","journal-title":"Academic Press, New York, 1972. 291 S., 32 Abb., 15 Tab., Preis $ 14.00. Starch - St\u00e4rke"},{"key":"2023111306000549000_2023.11.07.566117v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90298-W"},{"key":"2023111306000549000_2023.11.07.566117v1.33","first-page":"301","article-title":"Retinal pigment epithelial acid lipase activity and lipoprotein receptors: effects of dietary omega-3 fatty acids","volume":"100","year":"2002","journal-title":"Trans Am Ophthalmol Soc"},{"key":"2023111306000549000_2023.11.07.566117v1.34","doi-asserted-by":"publisher","DOI":"10.1042\/bj2620801"},{"key":"2023111306000549000_2023.11.07.566117v1.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914143116"},{"key":"2023111306000549000_2023.11.07.566117v1.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109703108"},{"key":"2023111306000549000_2023.11.07.566117v1.37","doi-asserted-by":"crossref","unstructured":"Esh Z , Suresh S , Ortolan D , Farnoodian M , Bose D , Ryu J , et al. LipidUNet-Machine Learning- Based Method of Characterization and Quantification of Lipid Deposits Using iPSC-Derived Retinal Pigment Epithelium. J Vis Exp. 2023(197).","DOI":"10.3791\/65503"},{"issue":"1","key":"2023111306000549000_2023.11.07.566117v1.38","doi-asserted-by":"crossref","first-page":"7293","DOI":"10.1038\/s41467-021-27488-x","article-title":"Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model","volume":"12","year":"2021","journal-title":"Nat Commun"},{"issue":"5","key":"2023111306000549000_2023.11.07.566117v1.39","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/cpt.2105","article-title":"Organic Anion Transporting Polypeptide Inhibition Dramatically Increases Plasma Exposure but not Pharmacodynamic Effect nor Inferred Hepatic Intracellular Exposure of Firsocostat","volume":"109","year":"2021","journal-title":"Clin Pharmacol Ther"},{"key":"2023111306000549000_2023.11.07.566117v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(63)91500-9"},{"issue":"2","key":"2023111306000549000_2023.11.07.566117v1.41","first-page":"159072","article-title":"The HDL Proteome Watch: Compilation of studies leads to new insights on HDL function","volume":"1867","year":"2022","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"2023111306000549000_2023.11.07.566117v1.42","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M009258"},{"key":"2023111306000549000_2023.11.07.566117v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(89)32664-9"},{"key":"2023111306000549000_2023.11.07.566117v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/ng1294-352"},{"key":"2023111306000549000_2023.11.07.566117v1.45","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.11-8353"},{"key":"2023111306000549000_2023.11.07.566117v1.46","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.exer.2018.08.005","article-title":"A cell culture condition that induces the mesenchymal-epithelial transition of dedifferentiated porcine retinal pigment epithelial cells","volume":"177","year":"2018","journal-title":"Exp Eye Res"},{"issue":"13","key":"2023111306000549000_2023.11.07.566117v1.47","doi-asserted-by":"crossref","first-page":"995","DOI":"10.2217\/imt-2022-0078","article-title":"Pegcetacoplan treatment for geographic atrophy due to age- related macular degeneration: a plain language summary of the FILLY study","volume":"14","year":"2022","journal-title":"Immunotherapy"},{"key":"2023111306000549000_2023.11.07.566117v1.48","doi-asserted-by":"crossref","unstructured":"Kang C . Avacincaptad Pegol: First Approval. Drugs. 2023.","DOI":"10.1007\/s40265-023-01948-8"},{"key":"2023111306000549000_2023.11.07.566117v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0336-8"},{"issue":"1","key":"2023111306000549000_2023.11.07.566117v1.50","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s40942-022-00431-y","article-title":"C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration","volume":"8","year":"2022","journal-title":"Int J Retina Vitreous"},{"key":"2023111306000549000_2023.11.07.566117v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.07.009"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.11.07.566117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:30:01Z","timestamp":1768455001000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.11.07.566117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,8]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2023.11.07.566117","relation":{},"subject":[],"published":{"date-parts":[[2023,11,8]]},"subtype":"preprint"}}