LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target.

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Choudhary, Mayur

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Ismail, Ebraheim N

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Yao, Pei-Li

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Tayyari, Faryan

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Radu, Roxana A

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Nusinowitz, Steven

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Boulton, Michael E

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Apte, Rajendra S

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Ruberti, Jeffrey W

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Handa, James T

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Tontonoz, Peter

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Malek, Goldis

dc.date.accessioned

2020-02-03T15:58:49Z

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2020-02-03T15:58:49Z

dc.date.issued

2020-01-16

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2020-02-03T15:58:43Z

dc.description.abstract

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.

dc.identifier

131928

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2379-3708

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2379-3708

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https://hdl.handle.net/10161/20053

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eng

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American Society for Clinical Investigation

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JCI insight

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10.1172/jci.insight.131928

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Mouse models

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Ophthalmology

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Retinopathy

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Therapeutics

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LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target.

dc.type

Journal article

duke.contributor.orcid

Malek, Goldis|0000-0003-0026-2388

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1

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School of Medicine

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Duke

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Duke Institute for Brain Sciences

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University Institutes and Centers

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Institutes and Provost's Academic Units

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Pathology

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Clinical Science Departments

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Ophthalmology, Vitreoretinal Diseases & Surgery

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Ophthalmology

pubs.publication-status

Published

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5

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