LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target
Mayur Choudhary, Ebraheim N. Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A. Radu, Steven Nusinowitz, Michael E. Boulton, Rajendra S. Apte, Jeffrey W. Ruberti, James T. Handa, Peter Tontonoz, Goldis Malek
Mayur Choudhary, Ebraheim N. Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A. Radu, Steven Nusinowitz, Michael E. Boulton, Rajendra S. Apte, Jeffrey W. Ruberti, James T. Handa, Peter Tontonoz, Goldis Malek
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Research Article Ophthalmology Therapeutics

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

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.

Authors

Mayur Choudhary, Ebraheim N. Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A. Radu, Steven Nusinowitz, Michael E. Boulton, Rajendra S. Apte, Jeffrey W. Ruberti, James T. Handa, Peter Tontonoz, Goldis Malek

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Figure 2

The LXR pathway is biologically active in AMD-vulnerable cells.

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The LXR pathway is biologically active in AMD-vulnerable cells. (A) LXR ...
(A) LXR activity in hRPE cells transfected with DR-4 luciferase reporter and siC (control, nontargeting siRNA), siNR1H3, siNR1H2, or siNR1H3/NR1H2 and treated with LXR agonists GW3965 and TO901317 or antagonist GSK2033. DMSO was used as a vehicle control. n = 3. Mean ± SEM shown. *P < 0.05 relative to siC DMSO; #P < 0.05 relative to drug siC–treated cells. Two-way ANOVA and Tukey’s multiple comparisons. Expression of LXR target genes fatty acid synthase (FASN) (B) and sterol regulatory element-binding protein 1 (SREBF1) (C) in hRPE cells in response to treatment with LXR agonists GW3965 and TO901317 and antagonist GSK2033. n = 3. Mean ± SEM. *P < 0.05 relative to siC DMSO; #P < 0.05 relative to drug siC–treated cells, 2-way ANOVA and Tukey’s multiple comparisons. (D) LXR activity in CECs transfected with DR-4 luciferase reporter and siC, siNR1H2, siNR1H2, or siNR1H3/NR1H2 cells and treated with LXR agonists GW3965 and TO901317 or antagonist GSK2033. DMSO was used as a vehicle control. n = 3. Mean ± SEM. *P < 0.05 relative to siC DMSO; #P < 0.05 relative to drug siC–treated cells. Two-way ANOVA and Tukey’s multiple comparisons. Expression of LXR target genes FASN (E) and SREBF1 (F) in CECs in response to treatment with LXR agonists GW3965 and TO901317 and antagonist GSK2033. n = 3. Mean ± SEM. *P < 0.05 relative to siC DMSO; #P < 0.05 relative to drug siC–treated cells, 2-way ANOVA and Tukey’s multiple comparisons.