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


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.





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Publication Info

Choudhary, Mayur, Ebraheim N Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A Radu, Steven Nusinowitz, Michael E Boulton, Rajendra S Apte, et al. (2020). LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target. JCI insight, 5(1). 10.1172/jci.insight.131928 Retrieved from https://hdl.handle.net/10161/20053.

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Goldis Malek

Professor of Ophthalmology

Age-related macular degeneration (AMD) is the leading cause of central vision impairment amongst the elderly in the Western World and is becoming increasingly prevalent World-wide.

Our lab is focused on investigating the cellular and molecular pathogenic mechanisms underlying the three clinical subtypes of AMD. We are driven by a desire to further understand signaling pathways critical in initiation and progression of AMD and hopefully identify therapeutic targets for this debilitating degenerative disease. Two major lines of investigation currently being followed concomitantly include (1) elucidating the role of lipid-mediated injury of retinal pigment epithelial cells and how this injury promotes pathogenic changes in Bruch’s membrane and drusen formation, key features of the dry AMD subtype, through activation of the nuclear receptors peroxisome proliferator activated receptors and liver-X receptors and (2) investigating the role of the xenobiotic responsive aryl hydrocarbon receptor in regulating cellular metabolism in two other subtypes of AMD, geographic atrophy and neovascular AMD.

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