{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:54:41Z","timestamp":1785455681270,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Project of Songjiang District","award":["2020SJ292"],"award-info":[{"award-number":["2020SJ292"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Effective treatments for age-related macular degeneration (AMD), the most prevalent neurodegenerative form of blindness in older adults, are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic changes. Liver X receptors (LXRs) play a critical role in intracellular homeostases, such as lipid metabolism, glucose homeostasis, inflammation, and mitochondrial function. However, its specific role in AMD and its underlying molecular mechanisms remain unknown. In this study, we investigated the effects of lipotoxicity in human retinal pigmental epithelial (ARPE-19) cells and evaluated how LXRs reduce 7-ketocholesterol (7KCh) lipotoxicity in RPE cells using models, both in vivo and in vitro. A decrease in oxidative lipid accumulation was observed in mouse retinas following the activation of the LXRs; this result was also confirmed in cell experiments. At the same time, LXRs activation reduced RPE cell apoptosis induced by oxysterols. We found that oxysterols decreased the mitochondrial membrane potential in ARPE-19 cells, while LXR agonists counteracted these effects. In cultured ARPE-19 cells, activating LXRs reduced p62, mTOR, and LC3I\/II levels, and the knockdown of LXRs elevated the expression of these proteins, indicating that activating LXRs could boost mitophagy. The findings of this study suggest LXR-active pharmaceuticals as a potential therapeutic target for dry AMD.<\/jats:p>","DOI":"10.3390\/nu14122473","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T03:01:22Z","timestamp":1655348482000},"page":"2473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Activation of LXRs Reduces Oxysterol Lipotoxicity in RPE Cells by Promoting Mitochondrial Function"],"prefix":"10.3390","volume":"14","author":[{"given":"Lirong","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital (Shanghai First People\u2019s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China"},{"name":"Shanghai Key Laboratory of Fundus Disease, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital (Shanghai First People\u2019s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China"},{"name":"Shanghai Key Laboratory of Fundus Disease, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital (Shanghai First People\u2019s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China"},{"name":"Shanghai Key Laboratory of Fundus Disease, Shanghai 200080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shanghai General Hospital (Shanghai First People\u2019s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China"},{"name":"Shanghai Key Laboratory of Fundus Disease, Shanghai 200080, China"},{"name":"Department of Ophthalmology, Shanghai Fourth People\u2019s Hospital Affiliated to Tongji University, Shanghai 200434, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.17219\/acem\/27093","article-title":"The Dry Form of Age-Related Macular Degeneration (AMD): The Current Concepts of Pathogenesis and Prospects for Treatment","volume":"24","author":"Pilecka","year":"2015","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1534\/genetics.116.195966","article-title":"Recombinant Haplotypes Narrow the ARMS2\/HTRA1 Association Signal for Age-Related Macular Degeneration","volume":"205","author":"Grassmann","year":"2017","journal-title":"Genetics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107849","DOI":"10.1016\/j.exer.2019.107849","article-title":"7-Ketocholesterol disturbs RPE cells phagocytosis of the outer segment of photoreceptor and induces inflammation through ERK signaling pathway","volume":"189","author":"Yang","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.4103\/jovr.jovr_182_17","article-title":"The Role of Mitochondria in AMD: Current Knowledge and Future Applications","volume":"12","author":"Kuppermann","year":"2017","journal-title":"J. Ophthalmic. Vis. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104756","DOI":"10.1016\/j.neuint.2020.104756","article-title":"Mitophagy in Parkinson\u2019s disease: From pathogenesis to treatment target","volume":"138","author":"Dernie","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.mito.2021.01.001","article-title":"Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions","volume":"57","author":"Mani","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1007\/s00018-018-2843-7","article-title":"Mitochondrial quality control in AMD: Does mitophagy play a pivotal role?","volume":"75","author":"Hyttinen","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nrd4280","article-title":"Liver X receptors in lipid metabolism: Opportunities for drug discovery","volume":"13","author":"Hong","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e131928","DOI":"10.1172\/jci.insight.131928","article-title":"LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target","volume":"5","author":"Choudhary","year":"2020","journal-title":"JCI Insight"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"42976","DOI":"10.1074\/jbc.M308420200","article-title":"Effects of apolipoprotein A-I on ATP-binding cassette transporter A1-mediated efflux of macrophage phospholipid and cholesterol: Formation of nascent high density lipoprotein particles","volume":"278","author":"Liu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/nature17674","article-title":"Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis","volume":"534","author":"Sallam","year":"2016","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.exer.2017.09.008","article-title":"Regulated efflux of photoreceptor outer segment-derived cholesterol by human RPE cells","volume":"165","author":"Storti","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.immuni.2009.06.018","article-title":"Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR","volume":"31","author":"Bensinger","year":"2009","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00005-012-0179-9","article-title":"Biological roles of liver X receptors in immune cells","volume":"60","author":"Valledor","year":"2012","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.tips.2012.03.013","article-title":"Liver X receptor biology and pharmacology: New pathways, challenges and opportunities","volume":"33","author":"Jakobsson","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.freeradbiomed.2015.08.010","article-title":"Mitochondrial regulation of macrophage cholesterol homeostasis","volume":"89","author":"Graham","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1089\/rej.2005.8.3","article-title":"Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging","volume":"8","author":"Lemasters","year":"2005","journal-title":"Rejuvenation Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1111\/joim.12951","article-title":"Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy","volume":"286","author":"Pedrelli","year":"2019","journal-title":"J. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"222","DOI":"10.7150\/thno.49860","article-title":"Selective autophagy of intracellular organelles: Recent research advances","volume":"11","author":"Li","year":"2021","journal-title":"Theranostics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.bbrc.2014.02.093","article-title":"LC3B is indispensable for selective autophagy of p62 but not basal autophagy","volume":"446","author":"Maruyama","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/brv.12103","article-title":"The role of mitochondria in mTOR-regulated longevity","volume":"90","author":"Wei","year":"2015","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.preteyeres.2014.03.002","article-title":"Cholesterol in the retina: The best is yet to come","volume":"41","author":"Pikuleva","year":"2014","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/00006982-199902000-00010","article-title":"Characterization of peroxidized lipids in Bruch\u2019s membrane","volume":"19","author":"Spaide","year":"1999","journal-title":"Retina"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.exer.2018.09.023","article-title":"The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on l ipid metabolism in the RPE","volume":"181","author":"Jun","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.bbalip.2016.07.013","article-title":"Lipids, oxidized lipids, oxidation-specific epitopes, and Age-related Macular Degeneration","volume":"1862","author":"Handa","year":"2017","journal-title":"Biochim. Et Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_28","first-page":"1306","article-title":"Uptake of cholesterol by the retina occurs primarily via a low density lipoprotein receptor-mediated process","volume":"12","author":"Tserentsoodol","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100057","DOI":"10.1194\/jlr.TR120000979","article-title":"Cholesterol homeostasis in the vertebrate retina: Biology and pathobiology","volume":"62","author":"Fliesler","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_30","first-page":"e54808","article-title":"An Alternative and Validated Injection Method for Accessing the Subretinal Space via a Transcleral Posterior Approach","volume":"118","author":"Parikh","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.freeradbiomed.2012.09.007","article-title":"Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent","volume":"53","author":"Li","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1007\/s00394-015-1142-4","article-title":"7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils","volume":"55","author":"Alba","year":"2016","journal-title":"Eur. J. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.bbrc.2013.11.081","article-title":"Induction of oxiapoptophagy, a mixed mode of cell death associated with oxidative stress, apoptosis and autophagy, on 7-ketocholesterol-treated 158N murine oligodendrocytes: Impairment by alpha-tocopherol","volume":"446","author":"Nury","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"973","DOI":"10.4161\/auto.24546","article-title":"Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration","volume":"9","author":"Kaarniranta","year":"2013","journal-title":"Autophagy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/nn.2575","article-title":"Autophagy gone awry in neurodegenerative diseases","volume":"13","author":"Wong","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1111\/j.1365-2990.2009.01034.x","article-title":"Review: Autophagy in neurodegeneration: Firefighter and\/or incendiarist?","volume":"35","author":"Rami","year":"2009","journal-title":"Neuropathol. Appl. Neurobiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/12\/2473\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:31:44Z","timestamp":1760139104000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/12\/2473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":36,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["nu14122473"],"URL":"https:\/\/doi.org\/10.3390\/nu14122473","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]}}}